Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
  • C08G77/04—Polysiloxanes
  • C08G77/22—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
  • C08G77/26—Polysiloxanes containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen nitrogen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
  • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
  • B01J20/10—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate
  • B01J20/103—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate comprising silica
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
  • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
  • B01J20/289—Phases chemically bonded to a substrate, e.g. to silica or to polymers bonded via a spacer
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3204—Inorganic carriers, supports or substrates
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
  • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
  • B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
  • B01J20/3251—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulphur
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3257—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one of the heteroatoms nitrogen, oxygen or sulfur together with at least one silicon atom, these atoms not being part of the carrier as such
  • B01J20/3259—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one of the heteroatoms nitrogen, oxygen or sulfur together with at least one silicon atom, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulfur with at least one silicon atom
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3268—Macromolecular compounds
  • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
  • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the subject of the present patent application relates to new peptide-silane "hybrid block” molecules, their synthesis, their use for the preparation of new hybrid peptide-silica materials, themselves usable in various applications, for example at the level of medical equipment, separation of complex products or even in nanoparticles for imaging.
• silica-based organic-inorganic hybrid materials obtained by sol-gel processes have attracted considerable attention in recent decades. Indeed, these materials constitute a spectacular class of products combining properties of organic moieties on inorganic matrices (Loy, DA et al, Chem rev 95, 1431-1442 (1995) and Corriu, Angew Chem Int. 39, 1376-1398 (2000)). Materials comprising both mesoporous silica structural characteristics and peptide properties constitute a new class of bioorganic-inorganic hybrid materials that would find their place in catalysis, separation or molecular recognition techniques, for example.
• Hybrid materials can be obtained by a direct synthetic approach of functionalization of silica, that is to say by copolymerization of tetraethylorthosilicates (TEOS) and an organotrialkoxysilane having the desired function.
• TEOS tetraethylorthosilicates
• the organic fragment can be introduced by grafting the latter onto the already structured silicic material (post-synthesis).
• neuroactive "silane peptides” are disclosed for producing films (thin films), which are then used to modulate the phenotype of the carcinoma strain cell line. embryonic PI 9.
• the Colin Przybylowski et al. (J. Mater Chem., 2012, 22, 10672-10683) relates to the design of biological interfaces that stimulate cell differentiation.
• WO 00/461238 relates to solid support synthesis in which the solid support is vaporizable at the time of cleavage.
• the article by Carmen Coll et al. (Angew Chem et al., Ed., 2011, 50, 2138-2140) relates to mesoporous silica nanoparticles functionalized by peptide strands, which peptide strands, under the action of a protease, release host molecules.
• US 2011/0092672 discloses nanoparticles comprising a peptide-silicic molecular fragment on the surface of the nanoparticles.
• antimicrobial / antibiotic / antifungal materials whose effectiveness is proven, or tools to diversify the hybrid materials obtained by C-terminal grafting of the peptide chain or on the side chain. peptides.
• the present invention allows a controlled grafting of molecules of interest with an extended potential both in terms of the grafting rate and the nature of the chemical bonds between the peptide chains and the silicic support by the use of perfectly defined hybrid elementary blocks. .
• the present invention also makes it possible to synthesize ab initio materials by using perfectly defined hybrid elementary blocks as precursors, thus enabling the production of new materials with innovative characteristics.
• the subject of the present invention relates to a peptide conjugate of formula
• A is a peptide fragment
• Y 2 , Y 3 which may be identical or different, each independently represent a hydrogen atom, a halogen atom or an OR 2 radical in which R 2 represents a hydrogen atom an aryl group or a saturated or unsaturated aliphatic hydrocarbon chain containing 1 to 6 carbon atoms optionally substituted with an aryl, halogen or hydroxyl group,
• n is an integer between 1 to 50, preferably 1 to 10.
• the peptide conjugate (I) is not one of the following structures H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) 3, H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) 2 F or H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) F 2 .
• A is a peptide fragment
• Y 2 , Y 3 which may be identical or different, each independently represent a hydrogen atom, a halogen atom or an OR 2 radical in which R 2 represents a hydrogen atom an aryl group or a saturated or unsaturated aliphatic hydrocarbon chain containing 1 to 6 carbon atoms optionally substituted with an aryl, halogen or hydroxyl group,
• n is an integer between 1 to 50, preferably 1 to 10, characterized in that:
• the peptide conjugate of formula (I), in which A is a linear peptide fragment comprises a single Si carried via an X group on the alpha amine at the N-terminus of the fragment A, then
• A is a peptide fragment selected from the group consisting of an antibiotic, an antimicrobial, an antifungal, an anti-inflammatory, a catalyst, a biological receptor ligand and an enzyme inhibitor, preferably an antibiotic, an antimicrobial, an antifungal an anti-inflammatory and a catalyst, more preferably an antibiotic, an antimicrobial, an antifungal and an anti-inflammatory, more preferably an antibiotic, an antimicrobial and an antifungal, more preferably an antibiotic and an antimicrobial;
• Yi is different from Y 2 and / or Y 3
• the peptide conjugate (I) is not one of the following structures H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) 3 , H-YGGFLR-NH-CH 2 -CH 2 - CH 2 - Si (OH) 2 F or H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) F 2 ..
• H-YGGFLR-NH-CH 2 -CH 2 -CH 2 - Si (OH) 3 H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) 2 F and H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) F 2 .
• the subject of the present invention relates to a peptide conjugate as described above characterized in that:
• Y 1 , Y 2 , Y 3 and X are as previously defined,
• Zi represents a side chain of a naturally occurring amino acid optionally substituted with a protecting group
• * represents the bond by which the fragment ( ⁇ ) is connected to the remainder of the peptide conjugate
• A is a peptide fragment selected from the group consisting of an antibiotic, an antimicrobial, an antifungal, an anti-inflammatory, a catalyst, a biological receptor ligand and an enzyme inhibitor, preferably an antibiotic, an antimicrobial, an antifungal an anti-inflammatory agent and a catalyst, more preferably an antibiotic, an antimicrobial agent, an antifungal agent and an anti-inflammatory agent, even more preferably an antibiotic, an antimicrobial agent and an antifungal agent, more preferably an antibiotic and an antimicrobial agent,
• Another object of the present invention relates to a method to synthesis of peptide conjugates defined above (including H-YGGFLR-NH-CH 2 structures - CH 2 -CH 2 -Si (OH) 3, H-YGGFLR- NH-CH 2 -CH 2 -CH 2 -Si (OH) 2 F and / or H-YGGFLR-NH-CH 2 -CH 2 -CH 2 -Si (OH) F 2 ), characterized in that it comprises the steps :
• X ' is a group X as defined above activated for example by means of an isocyanate, an azide, an aldehyde, an activated carboxylic acid such as an acyl chloride, or still a group -CO-NH-NH 2 , Y 1 , Y 2 , Y 3 are as defined as above.
• one aspect of the present invention relates to the use of a peptide conjugate defined above for incorporating a peptide strand of formula A into a silicic material or a metal oxide.
• the object of the present invention thus also relates to a synthetic mixture intended for the manufacture of hybrid peptide-silicic materials, characterized in that:
• said synthetic mixture contains at least one peptide conjugate as defined herein;
• said synthetic mixture optionally contains a preferentially organic or inorganic solvent ,.
• said synthetic mixture optionally contains another organic or inorganic monomer or polymer.
• said synthetic mixture optionally contains a catalyst for the polymerization.
• the object of the present invention further relates to a method ⁇ characterized by the following steps:
• step ii) condensation, optionally in situ, of the peptide conjugate obtained according to step i) on a support material, preferably selected from silica, mesoporous silica, silica nanoparticles, glass, a metal oxide, iii) step optional rinsing, preferably with a water-miscible organic solvent such as DMF, acetone, DMSO,
• the subject of the present invention relates to a ⁇ -silicic material grafted with peptide strands A as defined above that can be obtained by the ⁇ process defined above, with the exception of the cases where:
• the peptide strand A is a peptide sequence consisting of a poly-Ala, poly-Lys, poly-Met, poly-Glu (OBzl) or poly-Glu fragment,
• the support material consists of glass beads, or even consists of glass, and / or
• the ⁇ -silicic copolymeric material of peptide strands A does not comprise a protected YGGFLR fragment (Boc strategy in particular) or deprotected.
• the ⁇ -silicic copolymeric material of peptide strands A does not comprise a poly-Pro fragment, in particular a proline dimer, a proline trimer and / or a proline tetramer.
• the ⁇ -silicic copolymeric material of peptide strands A does not comprise a poly-Val fragment.
• the ⁇ -silicic copolymeric material of peptide strands A does not comprise any monomer, dimer or trimer of the protected GDEVDG fragment (Fmoc strategy in particular) or deprotected.
• the ⁇ -silicic copolymeric material of peptide strands A does not include the protected AAEAYAKELAEANMAKG fragment (Fmoc strategy in particular) or deprotected.
• the ⁇ -silicic copolymeric material of peptide strands A does not include the protected Cys-Lys-Gly-Arg-Gly-Asp fragment (Fmoc strategy in particular) or deprotected.
• the object of the present invention also relates to the use of the material ⁇ defined above for the catalysis of chemical reactions, the separation of products by chromatography, the functionalization of nanoparticles, the production of biocompatible matrix for the treatment of injuries and / or burns, obtaining material for electronic or ionic facilitated transport, fabrication of nanosensors, fabrication of printed circuits, preparation of antimicrobial surfaces, surface preparation promoting cellular regrowth to cover medical devices , or the silica particles used in the cosmetic formulation.
• An object of the present invention further relates to a method ⁇ characterized by the following steps:
• step i) activation of any of the groups Y 1 , Y 2 , and / or Y 3 of the peptide conjugate defined as above, preferably by hydrolysis, ii) condensation, optionally in situ, of the peptide conjugate obtained according to step i) with a silica precursor, such as silicic acid, a C 1 -C 10 silicate or tetraalkoxysilane, more particularly tetraethoxysilane, iii) optional rinsing step, preferably with a water-miscible organic solvent such as DMF, acetone, DMSO,
• a silica precursor such as silicic acid, a C 1 -C 10 silicate or tetraalkoxysilane, more particularly tetraethoxysilane
• step iii) optional rinsing step, preferably with a water-miscible organic solvent such as DMF, acetone, DMSO,
• the subject of the present invention relates to a silicic copolymer material ⁇ of peptide strands A as defined above which can be obtained by the ⁇ process, advantageously the ⁇ -peptide silicic copolymeric material of peptide strands A is a mesoporous silica, a film, a gel, a suspension or a solution.
• the silicic copolymer material ⁇ of peptide strands A does not comprise a poly-Ala, poly-Lys, poly-Met, poly-Glu (OBzl) or poly-Glu fragment.
• the silicic copolymer material ⁇ of peptide strands A does not comprise a poly-Pro fragment, in particular a proline dimer, a proline trimer and / or a proline tetramer.
• the silicic copolymer material ⁇ of peptide strands A does not comprise a poly-Val fragment, in particular a valine dimer.
• the silicic copolymer material ⁇ of peptide strands A does not comprise a protected YGGFLR fragment (Boc strategy in particular) or deprotected.
• the silicic copolymer material ⁇ of peptide strands A does not comprise any monomer, dimer or trimer of the GDEVDG fragment.
• the silicic copolymer material ⁇ of peptide strands A does not comprise the protected AAEAYAKELAEANMAKG fragment (Fmoc strategy in particular) or deprotected.
• the silicic copolymer material ⁇ of peptide strands A does not include the protected Cys-Lys-Gly-Arg-Gly-Asp fragment (Fmoc strategy in particular) or deprotected.
• the object of the present invention also relates to the use of the material ⁇ as defined above for the catalysis of chemical reactions, the separation of products by chromatography, the functionalization of nanoparticles, the production of biocompatible matrix for the treatment of wounds and / or burns, the manufacture of nanosensors, the manufacture of printed circuits, the preparation of antimicrobial surfaces, or the surface preparation promoting cellular regrowth to cover medical devices.
• Another subject of the present invention relates to a method ⁇ characterized by the following steps:
• TFA trifluoroacetic acid
• the subject of the present invention relates to a silicic copolymeric material ⁇ of peptide strands A as defined above which can be obtained by the ⁇ process.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise a poly-Ala, poly-Lys, poly-Met, poly-Glu (OBzl) or poly-Glu fragment.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise a poly-Pro fragment, in particular a proline dimer, a proline trimer and / or a proline tetramer.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise a poly-Val fragment, in particular a valine dimer.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise a protected YGGFLR fragment (Boc strategy in particular) or deprotected.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise any monomer, dimer or trimer of the GDEVDG fragment.
• the silicic copolymeric material ⁇ of peptide strands A does not comprise the protected AAEAYAKELAEANMAKG fragment (Fmoc strategy in particular) or deprotected.
• the silicic copolymeric material ⁇ of peptide strands A does not include the protected Cys-Lys-Gly-Arg-Gly-Asp fragment (Fmoc strategy in particular) or deprotected.
• the object of the present invention also relates to the use of the material ⁇ as defined above for the catalysis of chemical reactions, the separation of products by chromatography, the functionalization of nanoparticles, the production of biocompatible matrix for the treatment of wounds and / or burns, obtaining material for electronic or ionic facilitated transport, preparation of antimicrobial surfaces, surface preparation promoting cellular regrowth to cover medical devices, or silica particles entering the cosmetic formulation.
• conjugate refers to fragment "A" linked to the remainder of the molecule according to formula I.
• peptide should be understood as a polymer of amino acids, said amino acids being linked together by a peptide bond and / or pseudopeptide.
• a peptide generally contains between 2 and 80 to 100 amino acids, the upper limit not being clearly defined.
• Fragment A contains between 2 and 80 amino acids, more preferably between 3 and 40, and even more preferably between 4 and 20.
• spacer there is included a fragment comprising at least one atom.
• the spacer group contains at least one carbon atom.
• the spacer group makes it possible to reduce the steric hindrance between the peptide and the Si. More advantageously, the spacer group allows the silicate group to react with a limited annoyance of the fragment A. In addition, the spacer group allows a stable bond between the fragment A. and Si, while allowing the silicate moiety to react. It is therefore clear that the spacer group can not be an amino acid residue (i.e., a fused amino acid), or a peptide chain (i.e., a condensed peptide) .
• the spacer group comprises, or consists of, a saturated or unsaturated aliphatic hydrocarbon chain.
• the spacer group may furthermore include heteroatoms, in particular chosen from N, O, S or P, and may in addition be substituted, in particular by halogen atoms, or by hydroxyl groups, aryl groups, and alkyl groups. C 1 -C 4 , sulphates, amines, or phosphates.
• heteroatoms are present in the spacer moiety, preferably these heteroatoms are not directly connected to Si.
• the spacer group is a linear or branched C 1 -C 4 alkyl moiety. More preferably, the spacer group is a moiety - (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2 ) 4 -. Even more preferably, the spacer group is a - (CH 2 ) 3 - fragment.
• aliphatic saturated or unsaturated hydrocarbon chain is inclusive of alkyl type moieties C 1 -C 10 alkene, C 2 -Cio or alkyne, C 2 -C 10.
• C 1 -C 10 alkyl or "alkyl of 1 to 10 carbon atoms”, a saturated, cyclic, linear or branched aliphatic group containing from 1 to 10 carbon atoms. carbon, such as methyl, ethyl, isopropyl, tert-butyl, n-pentyl, etc.
• C2-C10 alkene or “alkene of 2 to 10 carbon atoms” group is meant for the purposes of the present invention, a linear or branched, mono- or polyunsaturated aliphatic group comprising from 2 to 10 carbon atoms.
• An alkene group according to the invention preferably comprises one or more ethylenic unsaturations.
• C2-C10 alkyne or “alkyne of 2 to 10 carbon atoms” is meant for the purpose of the present invention, an aliphatic group, linear or branched, comprising from 2 to 10 carbon atoms and at less a double unsaturation, that is to say a triple bond between two carbon atoms.
• An alkyne group according to the invention preferably comprises one or more double unsaturations.
• C 1 -C 10 alcohol a linear or branched, saturated aliphatic C 1 -C 12 alkyl group, as defined above, comprising at least one OH group.
• alcohols may be ethanol, isopropanol, propanol, butanol, isobutanol, t-butanol, etc.
• C3-C10 ketone a linear, cyclic or branched, saturated aliphatic C 1 -C 10 alkyl group, as defined above, comprising at least one carbonyl group inserted between two carbons.
• a ketone group may be acetone, butan-2-one or pentan-2-one.
• C1-C10 diketone two carbonyl groups, juxtaposed to each other or not, included in a C 2 -C 6 alkyl chain.
• a diacetone group may be acetyl acetone.
• C 3 -C 10 ester is understood to mean a C 1 -C 8 alkyl group covalently linked to another C 1 -C 6 alkyl group via a COO group, the total of the number of carbons being between 3 and 10.
• an ester group may be ethyl acetate.
• C 1 -C 10 ether a C 1 -C 9 alkyl group covalently linked to another C 1 -C 9 alkyl group via an oxygen the total number of carbons being between 2 and 10.
• an ether group may be diethyl ether.
• C 1 -C 10 haloalkyl a C 1 -C 10 alkyl group covalently linked to one or more halogen atoms, such as a chlorine or fluorine atom. , iodine or bromine.
• a haloalkyl group may be dichloromethane, chloroform or methyl iodide.
• C 1 -C 10 alkyl substituted with one or more nitriles a C 1 -C 10 alkyl group as defined above, covalently linked to one or more CN groups. , such as acetonitrile.
• cyclic lactam a C 3 -C 10 alkyl ring in which is inserted a CO-NH group, optionally substituted by a C 1 -C 10 alkyl group, such as a grouping methyl, ethyl, isopropyl, tert-butyl, n-pentyl, etc.
• An example of a cyclic lactam may be N-methyl-2-pyrrolidone (NMP).
• arylene represents a substituent of an organic compound derived from an aryl moiety in which at least one hydrogen atom has been removed from two carbons included in aryl.
• it is a phenethyl group.
• aryl group is meant an aromatic group, preferably comprising from 5 to 10 carbon atoms, comprising one or more rings and optionally comprising one or more heteroatoms (s), in particular oxygen, nitrogen or sulfur, such as for example a phenyl, furan, indole, pyridine, naphthalene, etc. group.
• silic material is understood to mean silica in these different forms, such as common commercial silica, for example as Corning®7980 silica, mesoporous silica, whether ordered or otherwise, and SiO 2 nanoparticles.
• the support is mesoporous silica, such as silica SBA, MCM, or HMS.
• metal oxide is meant metal oxides in the general sense such as Ti0 2 , Sn0 2 , ZnO, Fe 2 0 3 or mixtures thereof.
• an "antimicrobial activity" is the generic definition as understood by those skilled in the art, i.e., an effect relative to an antimicrobial agent.
• An antimicrobial agent is a substance that kills, slows growth or blocks the growth of one or more microbes.
• growth is understood within the scope of the present invention any cellular operation allowing a volumetric increase of the cell, cell division or cell reproduction.
• a microbe in the context of the present invention relates to any unicellular or multicellular pathogenic or parasitic organisms of other living organisms such as humans. Antibiotic activity
• Antibiotic activity is the generic definition as understood by those skilled in the art, that is to say an effect relative to an antibiotic agent.
• An antibiotic is a substance that kills, slows down growth, or blocks the growth of one or more bacteria.
• growth is understood within the scope of the present invention any cellular operation allowing a volumetric increase of the cell (bacterium), cell division (of the bacterium) or cell reproduction (of the bacterium).
• Antifungal activity is the generic definition as understood by those skilled in the art, i.e., an effect relative to an antifungal agent.
• Antifungal agent is a substance that kills, slows growth or blocks the growth of one or more fungi.
• growth it is understood within the scope of the present invention any cellular operation allowing a volumetric increase of the cell (fungus), cell division (of the fungus) or cell reproduction (of the fungus).
• anti-adhesive surfaces it is understood in the present invention that the surfaces described in the present manuscript, have an anti-adhesive effect, an anti-biofilm accumulated or not to a cell lysis effect, slowing of cell growth and / or or blocking the cell growth of microbes.
• antibiotic surfaces it is understood in the present invention that the surfaces described in the present manuscript, have an anti-adhesive effect, anti-biofilm accumulated or not to a bactericidal, bacteriostatic effect (the bacteria are lysed, can no longer divide or grow, and / or reproduce).
• Antifungal surfaces By “antifungal surfaces”, it is understood in the present invention that the surfaces described in the present manuscript, have an anti-adhesive effect, anti-biofilm accumulated or not to a cell lysis effect, slowing of cell growth and / or or blocking cell growth of fungi.
• a natural peptide is a peptide found in the environment without direct human intervention (except its extraction / isolation)
• a synthetic peptide is a peptide that is not found in the environment without direct human intervention (apart from its extraction / isolation).
• a synthetic peptide may be a sequence of a natural peptide in which at least one natural amino acid has been replaced by another, natural or synthetic.
• linear peptide it is understood that all the amino acids of the peptide are linked in their sequential order and that the peptide has an N-terminus and a C-terminus.
• cyclic peptide there is included an amino acid sequence having no N-terminus or C-terminus.
• a cyclic peptide can be linked by a side chain to the solid support, and then the general definition applies, or it can be connected to the support by one of its N-termini or C-terminal and then the cycle is closed through at least one side chain of an amino acid.
• S-S (or Se-Se) linked peptides which some term cyclic, are not included in the present cyclic peptide definition.
• Peptides possessing an N-terminal and a C-terminal, an S-S bridge or Se-Se are not considered in the present invention as cyclic peptides. They are included either in the synthetic peptides category or in the natural peptides category.
• a pseudopeptide is a peptide comprising at least one pseudopeptide bond.
• One of the two amino acids can therefore be unnatural or replaced by a non-amino acid analogue having functions required for the pseudopeptide bond, for example a diamine or a diacid of the malonate type.
• pseudopeptide bonds the various reactive groups of amino acids can also be protected.
• the term "pseudopeptides” thus also includes compounds having pseudopeptide whose reactive groups such as those of the side chains are protected.
• An example of a preferred pseudopeptide are the depsipeptides, that is to say the peptides of which at least one peptide bond has been replaced by an ester-COO- bond.
• amino acid should be understood as any molecule having at least one carboxylic acid, at least one amine and at least one carbon connecting this amine and this carboxylic acid.
• amino acids that can be used in the context of the present invention are the so-called “natural” amino acids and / or synthetic amino acids as defined below.
• amino acids of the present invention are of L-form.
• natural amino acid represents, inter alia, the following amino acids: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys), methionine (Met), proline (Pro), aspartic acid (Asp), asparagine (Asn), glutamine (Gin), glutamic acid (Glu), histidine (His), arginine (Arg) and lysine (Lys).
• the natural amino acids that are preferred according to the present invention are the amino acids of the L series. Synthetic amino acid
• synthetic amino acid includes all non-natural amino acids as defined above. These synthetic amino acids can be chosen from: ⁇ -alanine, allylglycine, tert-leucine, norleucine (Nie), 3-aminoadipic acid, 2-aminobenzoic acid, 3- aminobenzoic acid, 4-aminobenzoic acid, 2-aminobutanoic acid, 4-amino-1-carboxymethyl piperidine, 1-amino-1-cyclobutanecarboxylic acid, 4-aminocyclohexaneacetic acid, 1-amino acid cyclohexanecarboxylic acid, (1R, 2R) -2-aminocyclohexanecarboxylic acid, (1R, 2S) -2-aminocyclohexanecarboxylic acid, (1S, 2R) -2-aminocyclohexanecarboxylic acid, (1S, 2R) -2-aminocyclohexanecarboxy
• side chain of an amino acid represents the moiety carried by the ⁇ -carbon of an amino acid.
• side chains of naturally occurring amino acids such as glycine, valine, alanine and aspartic acid correspond to hydrogen, isopropyl, methyl and CH 2 COOH respectively.
• Side chains of other amino acids may be included in the definition of an amino acid side chain, such as those of the following amino acids: 4-amino-tetrahydropyran-4-carboxylic acid, allylglycine, diamino-butyric acid, diamino propionic acid , aminoserine, aminobutyric acid, amino butylglycine, phenylglycine, 4-chloro-phenylalanine, 4-fluoro-phenylalanine, 4-nitrophenylalanine, citrulline, cyclohexylalanine, thienylalanine, and the like.
• amino acids such as those of the following amino acids: 4-amino-tetrahydropyran-4-carboxylic acid, allylglycine, diamino-butyric acid, diamino propionic acid , aminoserine, aminobutyric acid, amino butylglycine, phenylglycine, 4-chloro-phenylalan
• the side chains of the amino acids may be protected by protecting groups (P) and more particularly N-protecting, O-protecting or S-protecting groups when these chains contain the corresponding heteroatoms.
• P protecting groups
• the protection of some of the reactive functions of the peptides is mandatory during the synthesis of said peptides.
• peptide synthesis is conventionally done by activating the carboxylic acid function of an amino acid, or an amino acid chain, by the use of a coupling agent. This activated acid is placed in the presence of an amino acid, or a chain of amino acids, whose terminal amine is not protected, thus resulting in the formation of an amide bond, also called peptide bond.
• the coupling conditions as well as the coupling agents used are very well known to those skilled in the art.
• Protecting groups (P) are also groups known to those skilled in the art. These protective groups and their use are described in books such as, for example, Greene, “Protective Groups in Organic Synthesis”, Wiley, New York, 2007 4th edition; Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1 to 8 (J. Wiley & sons, 1971 to 1996).
• a hydroxyl may be protected with a trityl group, or a carboxylic acid may be protected as a tert-butyl ester.
• a solid support synthesis it is the resin which serves as a protective group for the C-terminal carboxylic function.
• amino group (i.e. "alpha-amine") of the amino acid can be effected for example by a tert-butyloxycarbonyl group (hereinafter referred to as Boc-) or a group -9 -fluorenylmethyloxycarbonyl (hereinafter referred to as Fmoc-) represented by the formula:
• protection by the Boc-group can be obtained by reacting the amino acid with di-tert-butylpyrocarbonate (Boc 2 0).
• the amino acids obtained are synthetic until the removal of the protective group (s), thus releasing the so-called natural amino acid.
• Peptide synthesis is conventionally done by activating the carboxylic acid function of an amino acid, or an amino acid chain, by the use of a coupling agent.
• This activated acid is placed in the presence of an amino acid, or a chain of amino acids, whose terminal amine is not protected, thus resulting in the formation of an amide bond, also called peptide bond.
• the coupling conditions and the coupling agents used are very well known to those skilled in the art and described for example in books such as Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 2007 4th edition; Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1 to 8 (J. Wiley & sons, 1971 to 1996).
• the peptide conjugate of formula (I) is characterized in that the peptide fragment A is a linear natural peptide strand, a linear synthetic peptide strand, a linear protected natural peptide strand, a peptide strand.
• synthetic protected linear one strand linear natural pseudopeptide, a linear synthetic pseudopeptide strand, a linear protected natural pseudopeptide strand, or a linear protected synthetic pseudopeptide strand, or the peptide fragment A comprises or consists of a cyclic natural peptide fragment, a cyclic synthetic peptide fragment, a natural peptide fragment cyclic protected peptide fragment, cyclic cyclic pseudopeptide fragment, cyclic synthetic pseudopeptide fragment, cyclic protected pseudopeptide fragment or cyclic protected synthetic pseudopeptide fragment.
• the peptide conjugate of formula (I) is characterized in that Yi represents a fragment different from Y 2 , and / or Y 3 .
• Y 1 represents an OR 2 radical in which R 2 represents a hydrogen atom, an aryl group or a saturated or unsaturated aliphatic hydrocarbon chain containing from 1 to 6 carbon atoms optionally substituted with an aryl or halogen group, or hydroxyl and the groups Y 2 and / or Y 3 represent a hydrogen atom or a halogen atom.
• Y 1 represents a radical OR 2 in which R 2 represents a methyl or an ethyl, and the groups Y 2 and / or Y 3 represent a hydrogen atom or a halogen atom.
• Y 1 represents a radical OR 2 in which R 2 represents a methyl or an ethyl, and the groups Y 2 and / or Y 3 represent a hydrogen, chlorine or fluorine atom.
• Y 1 represents a radical OR 2 in which R 2 represents a methyl or an ethyl, and the groups Y 2 and / or Y 3 represent a chlorine or fluorine atom.
• the peptide conjugate of formula (I) is characterized in that Y 1 and Y 2 represent, independently of each other, a radical OR 2 in which R 2 represents a hydrogen atom an aryl group or a saturated or unsaturated aliphatic hydrocarbon chain containing from 1 to 6 carbon atoms optionally substituted by an aryl, halogen, or hydroxyl and the groups Y 3 represents a hydrogen atom or a halogen atom.
• Y 1 and Y 2 represent, independently of one another, a radical OR 2 in which R 2 represents a methyl or an ethyl, and the group Y 3 represents a hydrogen atom or a halogen atom. .
• Y 1 and Y 2 represent, independently of one another, a radical OR 2 in which R 2 represents a methyl or an ethyl, and the group Y 3 represents a hydrogen, chlorine or fluorine.
• Y 1 and Y 2 represent, independently of one another, a radical OR 2 in which R 2 represents a methyl or an ethyl, and the group Y 3 represents a chlorine or fluorine atom.
• the peptide conjugate of formula (I) is characterized in that the peptide fragment A comprises between 2 and 80 amino acids, preferably between 2 and 30 amino acids.
• the peptide conjugate of formula (I) is characterized in that the peptide fragment is an antibiotic, an antimicrobial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, a catalyst or a peptide fragment. structured, a biological receptor ligand and / or an enzyme inhibitor.
• the peptide conjugate of formula (I) is characterized in that the peptide fragment is an antibiotic, an antimicrobial, an antifungal, an anti-inflammatory, a catalyst, a receptor ligand and / or an enzyme inhibitor.
• the peptide conjugate of formula (I) is characterized in that the peptide fragment is an antibiotic, an antimicrobial, an antifungal and / or an anti-inflammatory. Even more advantageously, in one embodiment according to the present invention, the peptide conjugate of formula (I) is characterized in that the peptide fragment is an antibiotic, an antimicrobial and / or an antifungal.
• the peptide conjugate of formula (I) is characterized in that the peptide fragment is an antibiotic and / or an antimicrobial.
• the peptide conjugate of formula (I) is characterized in that the ratio of Si: N in mole included in the conjugate is between 1: 0.3 to 1: 100, preferentially between 1: 1 to 1:30, and even more preferably between 1: 2 and 1:15.
• the peptide conjugate of formula (I) is characterized in that it comprises at least one of the following fragments of formulas (II), (III) and / or (IV):
• Y 1 , Y 2 , and Y 3 are as defined above, X 1 , X 2 , X 3 , which are identical or different, each represent, independently of one another, a spacer group as defined above,
• Zi, Z 3 which may be identical or different, each represent, independently of one another, a side chain of a natural amino acid optionally substituted by a protective group,
• Z 2 represent a side chain of a natural amino acid substituted by X 2 or a bond
• R3 represents the N-terminal fragment of the peptide strand, a hydrogen atom or an N-protecting group
• R4 represents the C-terminal fragment of the peptide strand, a hydrogen atom, a group -NH 2 , a group -OR 5 , in which R 5 represents a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms , or an atom or a carbonyl activating group such as a halogen atom or a succinimide group,
• * represents the bond (s) by which the fragments are connected to the rest of the peptide conjugate.
• the groups Y 1 , Y 2 , and Y 3 represent OR 2 in which R 2 represents a hydrogen atom, an aryl group or a saturated aliphatic hydrocarbon chain containing from 1 to 6 carbon atoms. More preferably, R 2 represents a saturated aliphatic hydrocarbon chain containing from 1 to 6 carbon atoms, more preferably still selected from methyl, ethyl and propyl.
• the ⁇ silicic material is grafted with peptide strands A as defined above and is capable of being obtained by the ⁇ method, except where the X group is one any of the following groupings:
• bonds * represent the bonds linked to the peptide fragment and the bonds ** represent the bonds connected to Si.
• a particular embodiment according to the present invention thus also relates to a synthetic mixture intended for the manufacture of hybrid peptide-silicic antibiotic, antimicrobial, antifungal and / or anti-inflammatory materials, characterized in that:
• said synthetic mixture contains at least one peptide conjugate as defined herein;
• said synthetic mixture optionally contains a solvent, preferably organic alcohol such as a C1-C10, a ketone C 3 - Cio, a diketone C4-C10, a C 3 -Cio ester, ether, C 2 -C 10 , C 1 -C 10 haloalkyl, C 1 -C 10 alkyl substituted by one or more nitriles, cyclic lactam optionally substituted with C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted aryl, formamide substituted with 2-C 1 -C 10 alkyl, or inorganic such as water;
• a solvent preferably organic alcohol such as a C1-C10, a ketone C 3 - Cio, a diketone C4-C10, a C 3 -Cio ester, ether, C 2 -C 10 , C 1 -C 10 haloalkyl, C 1 -C 10 alkyl substitute
• said synthetic mixture optionally contains an additional organic or inorganic polymer selected from SiZ A4_ P P Q Z and A 3 _ q Si-Q RB and Z A 3 _ qIf-RB-SiZ Q A 3 _ q in which:
• Z and A are independently selected from hydrogen, chlorine, bromine or a hydroxy, methoxy, ethoxy, phenoxy, methyl, ethyl, propyl, isopropyl group;
• p 0, 1, 2 and 3;
• q 0, 1 and 2;
• RB represents a spacer arm preferably comprising a polyethylene glycol or poloxamer fragment (that is to say triblock copolymers of poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol)) having a mass of between 400 and 50,000. Daltons, preferably between 1000 and 20000 Daltons, more preferentially between 4000 and 15000 Daltons, (for example a triblock copolymer of the P123® or F127® type which are copolymers of poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) of about 5800 Daltons and 12600 Daltons respectively).
• a polyethylene glycol or poloxamer fragment that is to say triblock copolymers of poly (ethylene glycol) -poly (propylene glycol) -poly (ethylene glycol) having a mass of between 400 and 50,000. Daltons, preferably between 1000 and 20000 Daltons, more preferentially between 4000 and 15000 Daltons
• said synthetic mixture optionally contains a polymerization-enabling catalyst, if appropriate, preferably chosen from an inorganic acid, an organic acid, an inorganic base or an organic base, a metal or organometallic complex.
• a polymerization-enabling catalyst if appropriate, preferably chosen from an inorganic acid, an organic acid, an inorganic base or an organic base, a metal or organometallic complex.
• the synthetic mixture intended for the manufacture of hybrid antibiotic, antimicrobial and / or antifungal peptide-silicic materials as above characterized in that:
• said synthetic mixture optionally contains a solvent, preferably chosen from acetone, acetylacetone, ethyl acetate, THF, Et 2 O, iPr 2 O, CHCl 3 , CH 2 Cl 2 , MeCN, NMP, DMSO, toluene and DMF, R A OH in which R A may represent a hydrogen atom, a methyl, ethyl, propyl, isopropyl or butyl group.
• a solvent preferably chosen from acetone, acetylacetone, ethyl acetate, THF, Et 2 O, iPr 2 O, CHCl 3 , CH 2 Cl 2 , MeCN, NMP, DMSO, toluene and DMF, R A OH in which R A may represent a hydrogen atom, a methyl, ethyl, propyl, isopropyl or butyl group.
• the synthetic mixture intended for the manufacture of hybrid antibiotic, antimicrobial and / or antifungal peptide-silicic materials as above is characterized in that the said synthetic mixture contains an acidic catalyst allowing the polymerization, chosen from HF, HC1. , HBr, HI, HNO 3 , H 2 SO 4 , CH 3 COOH,
• the synthetic mixture intended for the manufacture of hybrid antibiotic, antimicrobial and / or antifungal peptide-silicic materials as above is characterized in that the said synthetic mixture optionally contains a basic catalyst allowing the polymerization, chosen from LiOH, NaOH, KOH, M 2 CO 3 (M representing Li, Na, K, Cs and 0.5Mg)
• the synthetic mixture intended for the manufacture of hybrid peptide-silicic antibiotic, antimicrobial and / or antifungal materials as above is characterized in that the said synthetic mixture optionally contains a MF-type catalyst for the polymerization wherein M is Li, Na, K, Cs and a quaternary amine substituted with one or more groups identical to or different from each other selected from Me, Et, Pr, Pr, Bu and 3 ⁇ 4u.
• M is Li, Na, K, Cs and a quaternary amine substituted with one or more groups identical to or different from each other selected from Me, Et, Pr, Pr, Bu and 3 ⁇ 4u.
• FIG. 2 mass spectrum of the LC peak of FIG. 1 obtained at 0.76
• the peptide is synthesized on a solid support using a CEM Liberty TM peptide synthesizer using microwave irradiation at 2450 MHz for the Fmoc / tert-butyl strategy coupling and deprotection steps.
• the synthesis was carried out on a scale of 0.25 mmol on Fmoc-Rink-amide polystyrene resin (390 mg, 0.640 mmol / g) at a scale of 0.25 mmol.
• the coupling reactions are carried out with an excess of 5 equivalents of amino acid (0.2M stock solution in DMF), 5 equiv. HBTU (0.5M stock solution in DMF), and 10 equiv. of DIEA (2M stock solution in the NMP solution).
• the cleavage of the resin is carried out for 90 minutes with stirring in trifluoroacetic acid. After evaporation of the solvent and trituration with ether, the peptide in the form of TFA (TFA, H-Gly-Phe-Glu-NH 2 ) salts is solubilized in 20 ml of a water / acetonitrile mixture, frozen and then freeze-dried. .
• This functionalization pathway involves the grafting of hybrid elementary blocks in the pores of mesostructured silicas by reaction of these blocks with the silanol groups present on the surface of the pores.
• This functionalization pathway in the pores of mesostructured silicas consists of the co-hydrolysis-polycondensation of a hybrid elementary blocks and of tetraalkoxysilane in the presence of surfactant.
• Fluorescent nanoparticles are prepared according to:
• Hybrid peptides ( II ) Si (OEt) 3 (CH 2 ) 3 NHCO-pAla 4 [NP] and hybrid peptides (2) Si (OEt) 3 (CH 2 ) 3 NHCO-PAla 5 c [RGD]) [ Lii] are first synthesized by Solid Phase Peptide Synthesis (SSPS) by the "Fmoc" strategy on trityl resin, then is carried out in solution the derivation with. trietfa.oxysilylpropyiisocyan.ate:
• the functional Sinds are prepared according to the following method:
• the mixture is heated at 65 ° C for 12 hours.
• the completion of the reaction was monitored by RP-HPLC, verifying the disappearance of the hybrid peptides.
• the mixture is cooled to room temperature and centrifuged at 3000 rpm. It is washed once with DMF and twice with dichloromethane and the product obtained is dried under vacuum for 12 hours.
• a colloidal solution based on a mixture of bis-silylated polyethylene glycol (PEG1000) and the test hybrid peptide coxysilyl (in this case the antimicrobial sequence Si (OEt) 3 (CH 2 ) 3 NHCO-Ahx-Arg (Pbf) -ATg (Pbf) -NH2) acid ethanol is prepared and poured into a petri dish under controlled relative humidity.
• the evaporation of the solvent causes the process of the mineral polymerization to form a three-dimensional network in the form of a flexible membrane.
• the membrane thus obtained is endowed with property carried by the bioactive peptide.
• this type of structure requires a 24-mer peptide linked to a lipid tail and a beta sheet forming a sequence to induce and maintain the triple helix-type tropocollagen assembly.
• the use of much shorter hybrid peptides (9 amino acids) has allowed the formation of irreversibly fixed triple helices, This gives a block which forms a hollow tube.
• TEM microscopy images show very regular tubes with diameters of 14 nm and a wall thickness of 3.5 nm. This type of matrix could be used as a coating at the cellular level imitation of implantable bonding.
• the synthesis of the hybrid peptides of collagen was carried out on a solid support using a "rink" amide resin and a Fmoc / tBu strategy.
• the trialkoxysilyl spacer fragment was grafted onto the side chain of the N-terminal lysine.
• hybrid hollow silica-peptide tubes were prepared by the method of injecting a colloidal solution of ethanol into water.
• the hydrolysis of trialkoxysilane in the hybrid peptides was carried out in a solution of ethanol acid (pH 4) at room temperature for one hour.
• the resulting sol is then injected into a solution of H 2 0 / EtOH (90/10) (pH 4, at room temperature) to a final concentration of 0.5 rng.ml 1 and incubated at 45 ° C for 24 h.
• H 2 0 / EtOH 90/10
• the polymerization of a tripeptide (Gly-Phe-Arg) sequence is presented to produce comb-like polymers based on a bis-silylated lysine scaffold with branched peptide sequences.
• the first step is the synthesis of the hybrid peptide having lysine at its N-terminus which is functionalized with isocyanatopropyldimethylchlorosilane.
• isocyanatopropyldimethylchlorosilane only one hydrolyzable function is present on each silicon atom.
• each function can react once, resulting in uncrosslinked, i.e. linear, polymers.
• hybrid peptide [OHMe 2 Si- (CH 2 ) 3 NHC0 2 Lys] -Phe-Giy-Arg-NH 2 is carried out according to a conventional SPPS Fmoc / tBu strategy, followed by a derivatization isat ion. on resin free friend groups ⁇ and a N-terminal lysine by isocyanatopropyl dimethylchlorosilyl. After cleavage, the hybrid peptide is obtained as a dimethylsiloxane derivative. Such a hybrid peptide may be characterized by LC / MS.
• the intermolecular cyclized hybrid peptide is detected (m / z 806) by ESI + LC / MS. This species is in equilibrium with the linear hybri.de peptide (m / z 824).
• comb-shaped silicon peptide polymers can be obtained using the same strategy as described in Example 8, without the need for lysine derivative. .
• the hybrid peptide [(OH) 2 MeSi- (CH 2 ) 3 NHCO] 2 -A.hx-Arg (Pbf) -Arg (Pbf> NH 2 was prepared in solution during the reaction with dichloro- (3- isocyanatopropyl) (methyl) silane and the protected peptide H-Ahx-Arg (Pbf) -Arg (Pbf) -NH 2.
• dichloro- (3- isocyanatopropyl) (methyl) silane and the protected peptide H-Ahx-Arg (Pbf) -Arg (Pbf) -NH 2.
• the sylil dichloromethyl derivative two hydrolysable functions are present on each silicon atom.
• each function one on each hybrid peptide
• the LC / MS indicates the presence of dimer and tri-mother testifying the beginning of the polymerization process, even in a water / acetonitrile TF A in proportion of 1/1 / 0.001.
• the Ahx-Arg-Arg sequence is known to have antibiotic properties.
• the H-Ahx-Arg (Pbf) -Arg (Pbf) -] SIH 2 sequence was prepared on "Sieber amide" resin.
• the trialkyloxysilyl group was grafted onto the terminal amine of the directly cleaved peptide of the resin, without purification thereof, with 3-isocyanatopropyltriethoxysilane (ICPTS).
• ICPTS is soluble in diethyl ether while the protected hybrid peptide is not, which has facilitated recovery of the desired product at the 100 mg scale.
• the density of peptides on the surface was estimated at 1.35 peptide per nm 2 by a spectrophotometric technique based on the reversible complexation of Coomassie brilliant bkeu dye with guanidine groups.
• the plates of the functionalized glasses were incubated in petri dishes at 37 ° C. in the presence of a suspension. of. Coli in exponential phase of growth. These plates were washed and covered with bromide of ethydium prior to microscopic examination. A control sample (glass plate not treated with the hybrid peptide, but covered with TEOS) was incubated and treated under the same conditions. The comparison shows that numerous colonies are present on the glass plate without hybrid peptide, while the plate which comprises the peptide has none.
• the Boc-Pro-Pro-Asp-Lys-NH 2 sequence is known to have catalysis properties in the aldol reaction.
• the sequence H-Pro-Pro-Asp (OtBu) -Lys-NH 2 was prepared on 2-chloro chlorotrityl resin ( "CT"), starting the synthesis by the anchoring of a lysine (Fmoc-I .ys- NH ..) by its side chain to the resin.
• CT 2-chloro chlorotrityl resin
• the synthesis of the peptide sequence is carried out by conventional coupling techniques on solid support.
• the peptide was removed from the resin by gentle cleavage.
• the trialkyoxysilyl group was grafted onto the free amine ⁇ of the lysine residue thus liberated, directly cleaved from the resin, without purification of the latter, with 3-isocyanatopropyltriethoxysilane (ICPTS).
• ICPTS is soluble in diethyl ether while the protected hybrid peptide is not, which has facilitated recovery of the desired product at the 100 mg scale.
• a yield of about 60-70% was obtained for a degree of purity higher than 95%.
• Mesoporous silica with controlled pore diameters was prepared by co-hydrolysis and polycondensation of TEOS with the previously synthesized hybrid peptide. (99.8 / 0.2 mol / mol) in the presence of Pluronic P123® (PEO20POP70PEO20) as surfactant.
• Pluronic P123® PEO20POP70PEO20
• the hybrid material was quantitatively obtained after the surfactant was removed by washing.
• the resulting white powder was treated with HMD S and TFA to remove the terbutyl and Boc groups.
• the HMDS made it possible to hydrophobize the surface of the obtained material as water is not recommended for the aldolization reaction.
• the mesoporous silica obtained has an ordered structure SBA-15® by the so-called XRD technique and by N 2 adsorption-desorption measurement.
• SBA-15® by direct comparison with a "conventional" mesoporous silica SBA-15®, the effective pore size obtained is not particularly different.
• the HMDS treatment decreases the surface area by 25% and 17% of the pore volume, which is ultimately still within an acceptable range in perspective of a conventional SBA-15® silica.
• the mesoporous silica obtained above was used as a supported catalyst (2 mol%) for enantioselective alkylation in the reaction of p-nitrobenzaldehyde with acetone. The reactions were followed by HPLC. No reaction was recorded for the conventional SBA-15 ⁇ mesoporous silica. The mesoporous silica functionalized with the protected peptide also provided a negative test result. In.

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