WO2006016560A1 - Complexe de porphyrine métallique - serumalbumine humaine recombinée, transporteur d’oxygène artificiel et substitut d’erythrocytes - Google Patents

Complexe de porphyrine métallique - serumalbumine humaine recombinée, transporteur d’oxygène artificiel et substitut d’erythrocytes Download PDF

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WO2006016560A1
WO2006016560A1 PCT/JP2005/014532 JP2005014532W WO2006016560A1 WO 2006016560 A1 WO2006016560 A1 WO 2006016560A1 JP 2005014532 W JP2005014532 W JP 2005014532W WO 2006016560 A1 WO2006016560 A1 WO 2006016560A1
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metal
human serum
serum albumin
recombinant human
complex
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Eishun Tsuchida
Teruyuki Komatsu
Naomi Ohmichi
Stephen Curry
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a recombinant human serum albumin-metal borphyrin complex, and an artificial oxygen carrier and a red blood cell substitute containing the recombinant human serum albumin.
  • the present invention relates to a complex of recombinant human serum albumin and metallophyllin in which histidine and a hydrophobic amino acid are introduced into subdomain IB, which is the heme binding site of human serum albumin, by genetic recombination technology, and the complex.
  • subdomain IB which is the heme binding site of human serum albumin
  • HSA Human serum albumin
  • a prosthetic molecule with a molecular weight of about 66,500 distributed in many places in the body, including blood and intercellular fluid, and a simple protein without sugar chains.
  • the 585 amino acid power including the disulfide bond is also constructed. Since it accounts for about 60% of blood protein, its colloid osmotic pressure plays a role in maintaining water balance inside and outside the blood vessel and maintaining vascular circulation. In addition, since it has the ability to bind non-specific multimolecules, it plays an important physiological role in the transport, storage, distribution and metabolism of various endogenous substances.
  • Hemin is incorporated into the subdomain IB of albumin, and is coordinated with 16 1 tyrosine and electrostatic between three basic amino acid (lysine 190, histidine 146, arginine 114) residues and the propionate side chain. Fixed by dynamic interaction.
  • the molecular environment surrounding the hemin binding site is composed solely of hydrophobic amino acid residues and is similar to the heme pocket of myoglobin (Mb). Under a nitrogen atmosphere, add sodium nithionite aqueous solution to this aqueous solution, and then add hemin to iron (Mb).
  • the research group of the present inventors found that iron (II) tetrafluoro-porphyrin having four hydrophobic substituents and having an axial base ligand covalently bound in the molecule is effective for hydrophobic interaction with albumin.
  • the resulting albumin heme complex is capable of adsorbing and desorbing oxygen in the same way as Hb and myoglobin (Mb) under physiological conditions (physiological saline, pH 7.3, 37 ° C).
  • Japanese Unexamined Patent Publication No. 8-301873, Japanese Unexamined Patent Publication No. 2003-40893 Japanese Unexamined Patent Publication No.
  • the mono-acidic acid is a vascular endothelial relaxing factor whose vascular endothelial permeability is low. ⁇ Do not erase nitrogen! Because there is no sudden fluctuation in blood pressure.
  • synthetic hem which functions as an oxygen coordination active center in these albumin monoheme complexes, has a special three-dimensional structure with four hydrophobic substituents and an axial base ligand in the molecule. It must be iron (II) tetraporphyrin, which is quite different from iron (II) protoporphyrin in natural Hb.
  • iron (II) tetraporphyrin which is quite different from iron (II) protoporphyrin in natural Hb.
  • the structural requirement for conferring oxygen coordination ability to the iron ( ⁇ ⁇ ) porphyrin of albumin-hemium complex is to first hold at least a proximal base covalently linked in the molecule. It was. For this reason, the synthesis process is multi-stage and has the disadvantages that mass production is difficult.
  • the present invention solves the above-mentioned problems of the prior art and can form a stable oxygen complex by introducing a metal porphyrin having no proximal base in the molecule. It is an object of the present invention to provide a metal borphyrin complex, and an artificial oxygen carrier and erythrocyte substitute containing the albumin metal complex.
  • the most important condition for imparting oxygen coordination ability to a metalloporphyrin is that imidazole serving as an axial base ligand is bound to the fifth coordination site of iron ( ⁇ ) porphyrin.
  • the inventors of the present invention have designed a molecular environment and developed a function for allowing imidazole, which is a proximal base, to be axially coordinated to the fifth coordination position without introducing an axial base into the metalloporphyrin molecule through a covalent bond.
  • the present inventors introduced histidine that acts as a proximal base into subdomain IB, which is a porphyrin-binding site of albumin, by genetic recombination technology, and oxygen
  • subdomain IB which is a porphyrin-binding site of albumin
  • oxygen By introducing a hydrophobic amino acid into the coordinating locus using genetic recombination technology and constructing an artificial hem pocket, the metal borphyrin complex immobilized inside via a coordinate coordination bond becomes a stable oxygen complex. It was found that the active center can be universalized not only with protoheme but also with a wide variety of metalloporphyrins, thereby completing the present invention.
  • the present invention is a heme binding site of human serum albumin.
  • subdomain IB at least one histidine coordinated to the 5-coordination locus of metal porphyrin was introduced by genetic recombination technology, and 161 tyrosine was replaced with a hydrophobic amino acid other than tyrosin.
  • Recombinant human serum albumin-porphyrin metal complex in which metal porphyrin is coordinated to recombinant human serum albumin is provided.
  • V ⁇ Needless to say, in this complex, the introduced histidine is coordinated to the pentacoordination site of the metalloporphyrin.
  • an artificial oxygen carrier oxygen infusion
  • the metal borphyrin has iron (II) or cobalt (II) as the central metal.
  • an erythrocyte substitute containing the recombinant human serum albumin-metal porphyrin complex of the present invention.
  • the metalloporphyrin has iron (II) or cobalt (II) as the central metal.
  • FIG. 1 shows Fe (III), Fe (II) (deoxy), Fe (II) (O) of recombinant human serum albumin (I142HZY161L) -iron (II) borphyrin complex (Oxy), Fe (II) (CO) (
  • the albumin metal-borphyrin complex of the present invention is a group in which at least one histidine is introduced by genetic recombination technology in subdomain IB, which is a heme binding site, and 161 tyrosine is substituted with a hydrophobic amino acid other than tyrosine. It can be obtained by binding metalloporphyrin to human serum albumin by axial coordination.
  • the recombinant human serum albumin used is preferably a combination of 142 isoleucine, 185 leucine, 138 tyrosine, 115 leucine, 139 leucine and / or 182 leucine strength histidine and 161 tyrosine substituted with a hydrophobic amino acid.
  • the recombinant human serum albumin may be a recombinant human serum albumin inserted at least one into subdomain IB, which is a heme binding site of human serum albumin.
  • hydrophobic amino acid for substituting 161 tyrosine glycine, alanine, norine, leucine, isoleucine, proline, tributophan or phenylalanine can be preferably used.
  • the metal porphyrin is preferably a metal protoporphyrin, a metal deuteroporphyrin, a metal diacetyl deuteroporphyrin, a metal mesoporphyrin, a metal diformyl porphyrin, a metal tetraphenyl porphyrin, or a metal otaethyl porphyrin .
  • the central metal is preferably iron or cobalt, particularly iron (II) or cobalt (II).
  • the recombinant human serum albumin metal volfilin complex of the present invention can bind and dissociate oxygen like Hb and Mb in water, and thus functions as a fully synthetic oxygen infusion (artificial oxygen carrier).
  • this recombinant human serum albumin not only serves as a substitute for red blood cells, but also preserves organs or tissues suitable for transplantation in a solution of the metal borphyrin complex, so that organs prior to transplantation can be stored. Or the organization can be stored safely and for a long time.
  • this recombinant human serum albumin-metal vorphyrin complex acts as a culture medium that promotes tissue growth, and if administered to the hypoxic site of the tumor, it can pass through fine capillaries where red blood cells cannot enter. Oxygenation of the oxygen site is realized, and then the tumor can be reduced or healed by immediately irradiating the affected area with radiation.
  • oxygen transfusion can be used for preoperative blood dilution, extracorporeal circulation such as cardiopulmonary bypass, perfusion fluid for transplanted organs, false Oxygen supply fluid to the blood site (myocardial infarction, cerebral infarction, respiratory failure, etc.), chronic anemia treatment agent, liquid ventilation recirculating fluid, use for rare blood type patients, transfusion rejection patients for religious reasons Is expected to be applied to animal medicine.
  • An artificial oxygen carrier oxygen infusion
  • Recombinant human serum albumin The concentration of metalloflurin complex varies depending on its use, but as a blood substitute (red blood cell substitute), a heme concentration of about 9.2 mMZL can be used, and other concentrations can be used.
  • the metal porphyrin is, for example, a complex of metal ions belonging to the 4th to 5th periods
  • the added value as a catalyst for the oxidation-reduction reaction, oxygen oxidation reaction or oxygen addition reaction is also high. Therefore, the porphyrin metal complex of the present invention has characteristics as a gas adsorbent, a redox catalyst, an oxygen oxidation reaction catalyst, and an oxygen addition reaction catalyst in addition to oxygen infusion.
  • the recombinant albumin of the present invention generally contains amino acid positions of the subdomain IB listed above. Or histidine is substituted or inserted into the amino acid in the vicinity thereof, or 161 thycin is substituted with a non-coordinating hydrophobic amino acid. Introduction of an amino acid at a specific position is accomplished by a variety of conventional means now known to achieve extensive recombination in albumin. Further, the recombinant albumin of the present invention can be prepared by mutating the DNA encoding albumin using conventional site-directed mutagenesis. This mutation is a small mutation that does not affect the original three-dimensional structure, physical properties, and characteristics of albumin. In addition, genetically modified albumin can be produced using a conventional culture method utilizing yeast.
  • mutagenesis can be performed using the Quick Change XL Site-Directed Mutagenesis Kit (STRATAGENE), and expression can be performed using the Picma Expression Kit (Invitrogen), CE Peterson et al., Bioc hemistry, 36 , 7012-7017 (1997).
  • the obtained recombinant human serum albumin can be purified by a conventional method, for example, column chromatography packed with Blue Sepharose 6 First Flow, followed by column chromatography packed with Cefacryl S200HR.
  • the albumin-metal borphyrin complex of the present invention can be prepared by the usual method described in Non-Patent Document 7, for example. If the metalloporphyrin is in the form of an iron (III) complex, use an appropriate reducing agent (sodium nithionite, ascorbic acid, etc.) and reduce the central metal from trivalent to divalent by a conventional method. For example, oxygen binding activity can be imparted. In either case, when it comes into contact with oxygen, a stable oxygen complex is rapidly formed. These complexes can adsorb and desorb oxygen according to the partial pressure of oxygen. This oxygen bond dissociation can be repeated reversibly and acts as an oxygen carrier.
  • an appropriate reducing agent sodium nithionite, ascorbic acid, etc.
  • the recombinant albumin metal volfilin complex of the present invention exhibits an effective function for many of the above-mentioned indications as an oxygen infusion solution, particularly in the case of an iron (II) or cobalt (II) complex, It can be used as a redox catalyst for homogeneous and heterogeneous systems, and as a gas adsorbent.
  • Recombinant albumin of the present invention Recombinant human serum albumin (I142H / Y161L) in which 142 isoleucine of human serum albumin is replaced with histidine and 161 tyrosine is replaced with leucine for the purpose of observing the oxygen-binding reaction of the metalloflurin complex of the present invention. )
  • the obtained mixed solution was washed with an ultrafiltration device (ultramolecular weight: 10,000), and concentrated and diluted with a 50 mM phosphate buffer aqueous solution repeatedly until the DMSO concentration became 0.1% or less.
  • the magnetic circular dichroism spectra of the recombinant albumin-iron (III) protoporphyrin complex aqueous solution thus prepared showed peaks at 366 (—), 40 2 (+), and 419 (—) nm. Was similar to the spectral pattern of met-Mb.
  • the imidazole group of 142 histidine is coordinated to central iron as an axial base, and it is considered that a deoxy form was obtained.
  • oxygen is passed through this recombinant human serum albumin (I142HZY161L) monoiron ( ⁇ ) protoporphyrin complex aqueous solution, the oxygen complex (oxy ) Type spectrum ( max : 412, 537, 573 nm) and aeration of carbon monoxide yielded a stable carbon monoxide complex (carbonyl) (max: 419, 538, 565 nm) (Fig. 1).
  • Figure 1 shows Fe (III), Fe (II) (deoxy), Fe (II) (O) (oxy) isomers of recombinant human serum albumin (I142HZY161L) -iron (II) borphyrin complex. , Fe (II) (CO) body
  • Recombinant albumin prepared in Example 1 (I142HZY161L) —iron (II) protoporphyrin complex aqueous solution is irradiated with leather flash (Nd: YAG laser, 532 nm, pulse width 6 ns) and equilibrated from the non-equilibrium state that occurs instantaneously.
  • leather flash Nd: YAG laser, 532 nm, pulse width 6 ns
  • recombinant human serum albumin (L185HZY161L) in which human serum albumin 185 leucine is replaced with histidine is treated with conventional site-specific
  • a recombinant human serum albumin (L 185H / Y161L) -iron (II) protoporphyrin complex was prepared according to the same procedure except that it was produced by mutagenesis and a conventional culture method using Pichia yeast.
  • the UV-visible absorption spectrum of this aqueous solution shows max: 422, 558 nm, which is a Mb deoxy-type spectrum.
  • Fe (ll) 5-coordinated high-spin complex was clarified by the similarities to the gold pattern. It is probable that the imidazole group of 185 histidine was coordinated to central iron as an axial base, and a deoxy form was obtained. When oxygen is bubbled through this aqueous complex solution, it immediately shifts to an oxygen complex type spectrum (max: 412, 530, 570 nm), and when carbon monoxide is bubbled, stable carbon monoxide complexes (max: 419, 537, 560 nm). )was gotten.
  • a recombinant human serum albumin (I142HZY161L) -cobalt ( ⁇ ) protoporphyrin complex was prepared in the same manner as in Example 1 except that cobalt ( ⁇ ) protoporphyrin was used instead of iron (III) protoporphyrin. .
  • the UV-visible absorption spectrum of this aqueous solution shows max: 406 and 558 nm, which is very similar to the cobalt Mb deoxy-type spectral pattern. The formation of the complex became obvious.
  • the imidazole group of 142 histidine was coordinated to central iron as an axial base, and it was considered that a deoxy form was obtained. When oxygen was bubbled through this aqueous complex solution, an immediate shift to an oxygen complex type vector (max: 426, 539, 578 nm) was obtained.
  • the recombinant human serum albumin-metal borphyrin complex according to the present invention is a porphyrin-binding site (sub-site) by gene recombination technology, even for metalloporphyrins that do not hold a proximal base covalently in the molecule.
  • the histidine introduced into domain IB) and the central metal are incorporated into the albumin through axial coordination, and human serum Al Since 161 tyrosine of bumine is substituted with a predetermined hydrophobic amino acid, a 5-coordinate high-spin complex can be formed and a highly stable oxygen-coordinated complex can be formed.
  • the recombinant human serum albumin according to the present invention fixes not only protohem, which is an oxygen binding site of Hb, but also a synthetic metalloporphyrin through an axial base coordination to express oxygen binding ability. be able to.
  • the artificial oxygen carrier (oxygen infusion solution) containing the recombinant human serum albumin metal volfilin complex of the present invention can be used as a blood substitute for highly safe blood for transfusion even when administered in vivo.
  • tissue culture solution To the transplanted organ or tissue preservation solution, tissue culture solution, tumor anti-cancer treatment sensitizer, preoperative blood dilution, extracorporeal circulation such as cardiopulmonary bypass, perfusion solution of transplanted organ, ischemic site It can be used as an oxygen supply solution (myocardial infarction, cerebral infarction, respiratory failure, etc.), a therapeutic agent for chronic anemia, and a circulating fluid for liquid ventilation.
  • oxygen supply solution myocardial infarction, cerebral infarction, respiratory failure, etc.
  • it is also useful as a gas adsorbent, oxidation-reduction catalyst, oxygen oxidation reaction catalyst, and oxygen addition reaction catalyst.

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Abstract

Complexe de porphyrine métallique - sérumalbumine humaine recombinée, ledit complexe comprenant une porphyrine métallique liée par le biais d’une liaison coordonnée à une sérumalbumine humaine recombinée ayant au moins un résidu d’histidine capable de se lier au site de coordination quintuple de la porphyrine métallique, qui a été transférée dans le sous-domaine IB (un site de liaison de l’hème) de la sérumalbumine humaine par un procédé de recombinaison génétique, et ayant une substitution de tyrosine à la position 161 par un aminoacide hydrophobe autre que la tyrosine.
PCT/JP2005/014532 2004-08-09 2005-08-08 Complexe de porphyrine métallique - serumalbumine humaine recombinée, transporteur d’oxygène artificiel et substitut d’erythrocytes Ceased WO2006016560A1 (fr)

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JP2004232518A JP2006045172A (ja) 2004-08-09 2004-08-09 組換えヒト血清アルブミン−金属ポルフィリン錯体、人工酸素運搬体および赤血球代替物

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JP2002500862A (ja) * 1997-12-03 2002-01-15 ニユー センチュリー フアーマシウテカルス，インコーポレイテッド 酸素運搬性アルブミンを基材とする血液代替組成物及び血液増量剤

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* Cited by examiner, † Cited by third party
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JP2002500862A (ja) * 1997-12-03 2002-01-15 ニユー センチュリー フアーマシウテカルス，インコーポレイテッド 酸素運搬性アルブミンを基材とする血液代替組成物及び血液増量剤

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