WO2016013828A1 - Mutant de domaine extracellulaire 1 de récepteur de chimiokines duffy sulfaté et utilisation associée - Google Patents

Mutant de domaine extracellulaire 1 de récepteur de chimiokines duffy sulfaté et utilisation associée Download PDF

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WO2016013828A1
WO2016013828A1 PCT/KR2015/007510 KR2015007510W WO2016013828A1 WO 2016013828 A1 WO2016013828 A1 WO 2016013828A1 KR 2015007510 W KR2015007510 W KR 2015007510W WO 2016013828 A1 WO2016013828 A1 WO 2016013828A1
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variant
disease
tyrosine
pharmaceutical composition
extracellular domain
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PCT/KR2015/007510
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Korean (ko)
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이형근
이준행
변석호
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연세대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons

Definitions

  • the present invention relates to extracellular domain 1 variants of one or more tyrosine sulfated Duffy chemokine receptors and uses thereof.
  • Chemokines is a relatively small secretory protein with a size of 8 to 15 Kd and collectively refers to substances causing proliferation, migration and activation of blood cells such as lymphocytes and neutrophils and vascular endothelial cells. About 40 chemokines have been found and they are known to exhibit activity through their respective receptors. Chemokines are known to be involved in the development and progression of many diseases, such as autoimmune diseases (eg, RA, SLE, Sjogren), and autoinflammatory diseases (crohn's Ds). It is known to be related. In addition, fatal rejection in organ or tissue transplantation is also mediated by chemokines. Accordingly, research is being actively conducted to develop various kinds of inhibitors capable of inhibiting chemokine activity.
  • autoimmune diseases eg, RA, SLE, Sjogren
  • autoinflammatory diseases crohn's Ds
  • DARCs Duffy chemokine receptors
  • DARCs are also known as decoy receptors, which are mainly present in vascular endothelial cells and are involved in the regulation of inflammatory responses, angiogenesis, etc. (Blood. (2010) 115 (26): 5289-5299).
  • Angiogenesis is an exaggeration that must be involved in the wound repair process, which is essential for the rejuvenation of wounded tissue.
  • cells die and inflammatory reactions occur due to the destruction of blood vessels.
  • devascularization of blood components activation of platelets, blood coagulation, biological media such as kallikrein, thrombin, plasmin, etc. It goes through a series of processes called formation.
  • new tissue is formed at the site of the wound, and the synthesis and reconstitution of the substrate of the cell occurs, so that the wounded tissue is healed to function again.
  • a complex cascade reaction of endothelial cells, inflammatory cells, or immune-related granulocytes, mast cells, and platelets is performed, and a defense mechanism that inhibits foreign body penetration into the wound site is performed.
  • epidermal cells, macrophages, endothelial cells and fibroblasts secrete various growth factors to promote cell division for the formation of new tissues, and at the same time epidermal cells, endothelial cells,
  • the reorganization of the cell matrix occurs by the matrix proteins of various cells secreted by fibroblasts, thereby completing wound healing and forming new tissues at the wound site.
  • An important phenomenon that accompanies this complex wound healing process is the formation of new blood vessels.
  • Blood vessel formation plays a role in helping the tissues regenerate and function normally as new tissues are formed during wound healing, supplying appropriate oxygen and nutrients to these tissues.
  • Such agents that can promote angiogenesis play a very important role in the postoperative recovery process in various fields such as plastic surgery and cardiology, which are in charge of surgery in addition to wound healing. Development of a formulation for the situation is not active.
  • the inventors of the present invention have completed the present invention by using an Duffy chemokine receptor having high binding strength with chemokines, and trying to develop an accelerator capable of controlling the inflammatory response and simultaneously promoting blood vessel formation.
  • the present invention has been made to solve the above-mentioned problems in the prior art, to provide an extracellular domain 1 variant of the sulfated Duffy chemokine receptor that can regulate the inflammatory response and at the same time promote the formation of blood vessels It is done.
  • angiogenesis refers to both a series of processes in which new blood vessels are made and / or a series of processes in which existing blood vessels are extended, and migration of endothelial cells constituting blood vessels It may proceed through the process of invasion through the extracellular matrix (ECM), an intercellular barrier, proliferation, differentiation into blood vessels (tube production), and the like.
  • ECM extracellular matrix
  • endothelial cell refers to all cells that make up the endothelium aligned on the inner surface of blood vessels, which may include capillaries, coronary vessels, endocardium, veins, arterial vessels, etc. If it is a cell constituting is not limited thereto.
  • wound means any damage to which skin, tissue, organs, etc., are torn, penetrated, cut, cracked, or ruptured as a result of a disease, accident, surgery, or the like.
  • the present invention provides an extracellular domain 1 variant of the duffy chemokine receptor, wherein 1-3 tyrosine of the extracellular domain 1 of the Duffy chemokine receptor is sulfated.
  • the extracellular domain 1 of the Duffy chemokine receptor may include the amino acid sequence of SEQ ID NO: 1, but is not limited to the extracellular domain 1 of the Duffy chemokine receptor.
  • the tyrosine may be the 6th, 32nd, or 43rd amino acid, or may be a combination of two or more thereof, but is not limited thereto.
  • the present invention also provides a pharmaceutical composition comprising an extracellular domain 1 variant of the Duffy chemokine receptor.
  • the pharmaceutical composition may be used for promoting angiogenesis, for treating inflammatory diseases, for treating wounds, and the like.
  • the pharmaceutical composition for promoting angiogenesis is a non-union of bone. It can be used to treat a variety of wounds such as malunion, skin wound defects, and ischemic diseases.
  • the skin defect may be caused by diabetes, ischemic disease, Burger's disease, etc.
  • the ischemic disease may include, but is not limited to, myocardial infarction and stroke.
  • the pharmaceutical composition for treating inflammatory diseases may be used for various diseases such as asthma, atherosclerosis, glomerulonephritis, pancreatitis, restenosis, rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, inflammatory bowel disease, Crohn's disease, transplant rejection, etc. If the disease can be treated through the regulation of angiogenesis and / or inflammatory response is not limited thereto.
  • the inflammatory diseases are ischemic lesions caused by embolisms such as chronic skin ulcer and pressure sore, cellulitis, atherosclerotic lesions (ischemic disease from atherosclerotic lesions), blood clots, etc.
  • ischemic disease from embolic lesions ischemic brain disease and lesions, including stroke, visceral ischemic syndrome, ocular ischemic syndrome in the eye or retina, Peripheral vascular disease (peripheral vascular disease, peripheral artery occlusive disease, peripheral obliterative arteriopathy), diabetic vasculopathy.
  • it can be used for adjuvant therapy for cellulitis, or for adjuvant and / or postoperative management for skin transplantation, for skin transplantation in deep burn patients.
  • the pharmaceutical composition may be characterized in that the capsule, tablets, granules, injections, ointments, powder or beverage form, the pharmaceutical composition may be characterized in that it is intended for humans.
  • Routes of administration of the pharmaceutical compositions according to the invention are not limited to these, but are oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral release is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • compositions of the present invention may be used in the form of oral dosage forms, such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be used as oral administration binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc.
  • buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used.
  • the formulation of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And others, solutions, suspensions, tablets, capsules, sustained release preparations and the like.
  • suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • the pharmaceutical compositions of the present invention vary depending on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed.
  • the dosage of the pharmaceutical composition may be appropriately selected by those skilled in the art depending on the patient's condition, weight, degree of disease, drug form, route of administration and duration, and 0.0001 to 50 mg / kg or It may be administered at 0.001 to 50 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
  • the present invention also provides an angiogenesis treatment method, an inflammatory disease treatment method, a wound treatment method, etc. using the extracellular domain 1 variant of the Duffy chemokine receptor.
  • the extracellular domain 1 variant of one or more tyrosine sulfated Duffy chemokine receptors can regulate the inflammatory response and promote blood vessel formation, so plastic surgery, cardiology, etc. It is expected to be widely used in the field.
  • Figure 2 shows the results of electrophoresis confirming that the variant DNA of the extracellular domain 1 of the Duffy chemokine receptor is inserted into the pET41a vector normally according to an embodiment of the present invention.
  • Figure 3 shows the results confirmed by SDS-PAGE that the extracellular domain 1 of the Duffy chemokine receptor normally sulfated according to an embodiment of the present invention.
  • Figure 4 is a result of confirming the inflammatory response control capacity and blood vessel formation promoting ability of the extracellular domain 1 variant of Duffy chemokine receptor according to an embodiment of the present invention.
  • Extracellular domain 1 of the duffy chemokine receptor SEQ ID NO: 1
  • primers were synthesized to sulfate each of the three tyrosine groups present in MASSGYVLQAELSPSTENSSQLDFEDVWNSSYGVNDSFPDGDYDANLEAAAPCHSCLEAAAPCHSC). Primer sequences are shown in Table 1 below.
  • variant 1 (DaMT1) of the first position tyrosine (sixth amino acid) of the extracellular domain 1 of the Duffy chemokine receptor
  • 1.1F, 1.1R, 1.2F, 1.2R, 1.3F, 1.3R, 1.4F, 1.4R , 1.5F, and 1.5R primer sets were used and 1.1F, 1.1R, 1.2F, 1.2R, 1.3F, 1.3R were prepared to prepare variant 2 (DaMT2) of the first and second position tyrosine (32th amino acid).
  • Each primer was prepared by mixing at a concentration of 10 pmole, polymerase chain reaction was performed by mixing 5uL of dNTP, 5uL of 10X Taq buffer, 0.5uL of Ex Taq, and 35.5uL of tertiary distilled water to 4uL of the mixed primers.
  • the polymerase chain reaction was performed after the first DNA denaturation step (94 ° C., 5 minutes), 30 seconds at 94 ° C. (DNA denaturation step), 30 seconds at 52 ° C. (DNA annealing step), and 30 seconds at 72 ° C. (DNA extension). ) was repeated 55 times and reacted at 72 ° C. for 5 minutes.
  • Secondary polymerase chain reaction was performed using DNA amplified by the overlapping polymerase chain reaction as a template. Secondary polymerase chain reaction was performed by amplifying DNA 1.25uL, 1.1p primer 10pmol 0.5uL, 1.1R primer 10pmol 0.5uL, dNTP 5uL, 5X band 10uL, 10X taq buffer 5uL, Ex Taq 0.5uL, and tertiary distilled water 27.25uL Mix, and after the first DNA denaturation step (94 ° C., 5 minutes), 30 seconds at 94 ° C. (DNA denaturation step), 30 seconds at 50 ° C. (DNA annealing step), and 30 seconds at 72 ° C. (DNA extension) was repeated 23 times and reacted at 72 ° C. for 5 minutes.
  • first DNA denaturation step 94 ° C., 5 minutes
  • 30 seconds at 94 ° C. DNA denaturation step
  • 30 seconds at 50 ° C. DNA annealing step
  • Amplified DNA was checked for DNA size by 1.5% agarose gel electrophoresis (agarosegel electophoresis). After gel extraction (gel extraction) to confirm DNA sequence, it was inserted into pGEM T easy vector and transformed into Escherichia coli DH5a, and then the amplified vector was extracted to check whether the amplified DNA was inserted by electrophoresis. It was. The results are shown in FIG.
  • DNA sequencing was performed using a vector in which the amplified DNA was inserted. As a result of sequencing analysis, it was confirmed that a total of three variants in which the TAT sequence of each tyrosine position was converted to the TAG sequence was normally prepared.
  • Variant DNAs of the extracellular domain 1 of the three Duffy chemokine receptors prepared by the method of Example 1.2 were inserted into expression vectors (pET41a) containing the GST-His tag, respectively, and their size was confirmed by electrophoresis. The results are shown in FIG. The produced vector was finally transformed into E. coli BL21.
  • the pET41a vector into which each variant DNA was inserted was transformed into E. coli BL21, and the pSUPAR6-L3-3SY vector was further transformed into the transformed E. coli BL21.
  • the pSUPAR6-L3-3SY vector was available from Scripps Laboratories.
  • the transformed E. coli was inoculated in 5 mL of 2YT liquid medium, pre-incubated for 18 hours in a 37 ° C shaking incubator, inoculated to 1% in YT liquid medium containing 10 mM sulfotyrosine and shaken at 37 ° C. Main culture was incubator. When the OD600nm value reached 1.0, IPTG was added so as to have a final concentration of 1 mM and incubated at 30 ° C. for 20 hours.
  • the cultured cells were centrifuged (13,000 g, 1 minute) to remove the supernatant, and the cells from which the supernatant was removed were subjected to cell resuspensin buffer (50 mM Tris-HCl pH 8.0, 2 mM EDTA, 0.1% Triton X-100). 1 mL was added and mixed well. And sonication (breaking 30 seconds per 1ml buffer and 2 minutes rest twice) to break the cells, centrifugation (14,000g, 20 minutes) to recover only the supernatant containing protein. Proteins were separated from the supernatant recovered using His column. The isolated protein was quantified and confirmed by electrophoresis using 10% SDS-PAGE. As a control, extracellular domain 1 (DARCex1) of the Duffy chemokine receptor, which was not sulfated, was used. The results are shown in FIG.
  • Example 3 Duffy Chemokines Extracellular domain of receptor 1 Variant Inflammatory response Controllability And blood vessel formation promoting ability
  • Administration was at a concentration of 20 ug / mL.
  • the control group (FIG. 4A) administered only with GST produced little infiltration of inflammatory cells and formation of neovascularization
  • the experimental group administered with variants (FIG. 4B) infiltrated inflammatory cells at the lower right corner.
  • This increased brightly observed confirmed that the increased blood vessel formation at the top.
  • the experimental group (FIG. 4D) the formation of new blood vessels is increased, and the infiltration of inflammatory cells is increased, thereby increasing the cornea. It became cloudy and confirmed that it was dark overall.
  • Example 3.1 a separation cornea in a manner of using the easy-spinTM Total RNA extraction kit (iNtRON) to extract RNA, and, FastAQ TM One-Step SYBR Green qRT-PCR Kit (Excellgen) using a vascular endothelial growth factor Quantitative PCR (qPCR) of vascular endothelial growth factor A and vascular endothelial growth factor C was performed.
  • the results are shown in FIG.
  • the extracellular domain 1 variants of the sulfated Duffy chemokine receptor are easy to penetrate into vascular cells or inflammatory cells, and therefore, do not directly stimulate blood vessels, but after binding to chemokines to help the formation of blood vessels and / or blood vessels. Infiltrating into inflammatory cells increases the concentration of chemokines within the cells, thereby promoting the formation of new blood vessels, as well as controlling the inflammatory response. In addition, it was confirmed that the formation of new blood vessels was more actively promoted in the case of DaMT2 and DaMT3, which are complex gene variants than DaMT1, which is a single gene variant, through which the cell penetration and / or chemokine binding capacity of the complex gene was increased. I could confirm that.
  • the extracellular domain 1 variants of sulfated Duffy chemokine receptors produce blood vessels such as non-union of bone, malunion, skin wound defects and ischemic disease. It can be found that it can be widely used for various diseases that are needed, can be used for treating various wounds, and can be used to prevent or treat inflammatory diseases because it can control inflammatory diseases.
  • the extracellular domain 1 variant of one or more tyrosine sulfated Duffy chemokine receptors can regulate the inflammatory response and promote blood vessel formation, so plastic surgery, cardiology, etc. It is expected to be widely used in the field.
  • Extracellular domain 1 of duffy chemokine receptor Extracellular domain 1 of duffy chemokine receptor:
  • SEQ ID NO: 2 (1.1F): AAA GGA TCC GCC TCC TCT GGG TAG GTC CTC CAG GCG GAG
  • SEQ ID NO: 3 (1.2F): CTC TCC CCC TCA ACT GAG AAC TCA AGT CAG CTG GAC TTC
  • SEQ ID NO: 4 (1.3F): GAA GAT GTA TGG AAT TCT TCC TAT GGT GTG AAT GAT TCC
  • SEQ ID NO: 5 (1.4F): TTC CCA GAT GGA GAC TAT GGT GCC AAC CTG GAA GCA GCT
  • SEQ ID NO: 6 (1.5F): GCC CCC TGC CAC TCC TGT CTC GAG AAA AAA AAA AAA AAA AAA AAA AAA AAA;
  • SEQ ID NO: 7 (1.1R): TTT TTT CTC GAG ACA GGA GTG GCA GGG GGC AGC TGC TTC
  • SEQ ID NO: 8 (1.2R): CAG GTT GGC ACC ATA GTC TCC ATC TGG GAA GGA ATC ATT
  • SEQ ID NO: 9 (1.3R): CAC ACC ATA GGA AGA ATT CCA TAC ATC TTC GAA GTC CAG
  • SEQ ID NO: 10 (1.4R): CTG ACT TGA GTT CTC AGT TGA GGG GGA GAG CTC CGC CTG
  • SEQ ID NO: 11 (1.5R): GAG GAC CTA CCC AGA GGA GGC GGA TCC TTT TTT TTT TTT TTT TTT
  • SEQ ID NO: 12 (2.1F): GAA GAT GTA TGG AAT TCT TCC TAG GGT GTG AAT GAT TCC
  • SEQ ID NO: 13 (2.1R): CAC ACC CTA GGA AGA ATT CCA TAC ATC TTC GAA GTC CAG
  • SEQ ID NO: 14 (3.1F): TTC CCA GAT GGA GAC TAG GGT GCC AAC CTG GAA GCA GCT
  • SEQ ID NO: 15 (3.1R): CAG GTT GGC ACC CTA GTC TCC ATC TGG GAA GGA ATC ATT

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Abstract

L'invention concerne : un mutant de domaine extracellulaire 1 d'un récepteur de chimiokines duffy dans lequel au moins une tyrosine est sulfatée ; ainsi que son utilisation, le mutant selon l'invention présentant une propriété de pénétration cellulaire élevée et, en même temps, une propriété de liaison aux chimiokines élevée, ce qui permet de l'utiliser largement pour réguler efficacement une réaction inflammatoire et/ou favoriser l'angiogenèse.
PCT/KR2015/007510 2014-07-21 2015-07-20 Mutant de domaine extracellulaire 1 de récepteur de chimiokines duffy sulfaté et utilisation associée WO2016013828A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002338600A (ja) * 2001-05-17 2002-11-27 Japan Science & Technology Corp Ｈｉｖ−１の感染を抑制するポリペプチド
KR20030091953A (ko) * 2000-12-29 2003-12-03 사비언트 파마슈티컬즈 인코퍼레이티드 황산화된 부분을 함유하는 에피토프를 포함하는 분리된분자, 그러한 에피토프에 대한 항체, 및 그들의 용도
KR20070091268A (ko) * 2004-10-21 2007-09-10 더 뉴욕 블러드 센터, 인코포레이티드 케모킨용 더피 항원 수용체 및 이의 용도
JP2010531655A (ja) * 2007-07-03 2010-09-30 ファリス バイオテック ゲーエムベーハー Ｃｘｃケモカイン受容体４（ｃｘｃｒ４）拮抗性ポリペプチド

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002033860A (ja) 2000-07-14 2002-01-31 Murata Mach Ltd ファクシミリ装置
US20050069955A1 (en) 2003-06-30 2005-03-31 Daniel Plaksin Antibodies and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030091953A (ko) * 2000-12-29 2003-12-03 사비언트 파마슈티컬즈 인코퍼레이티드 황산화된 부분을 함유하는 에피토프를 포함하는 분리된분자, 그러한 에피토프에 대한 항체, 및 그들의 용도
JP2002338600A (ja) * 2001-05-17 2002-11-27 Japan Science & Technology Corp Ｈｉｖ−１の感染を抑制するポリペプチド
KR20070091268A (ko) * 2004-10-21 2007-09-10 더 뉴욕 블러드 센터, 인코포레이티드 케모킨용 더피 항원 수용체 및 이의 용도
JP2010531655A (ja) * 2007-07-03 2010-09-30 ファリス バイオテック ゲーエムベーハー Ｃｘｃケモカイン受容体４（ｃｘｃｒ４）拮抗性ポリペプチド

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