WO2023128507A1 - Banque de peptides n-formyl hexamères et ses utilisations - Google Patents

Banque de peptides n-formyl hexamères et ses utilisations Download PDF

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WO2023128507A1
WO2023128507A1 PCT/KR2022/021294 KR2022021294W WO2023128507A1 WO 2023128507 A1 WO2023128507 A1 WO 2023128507A1 KR 2022021294 W KR2022021294 W KR 2022021294W WO 2023128507 A1 WO2023128507 A1 WO 2023128507A1
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formyl
cells
peptide
amino acids
library
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PCT/KR2022/021294
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English (en)
Korean (ko)
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이태훈
김재왕
김영은
장연호
정민규
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(주)노바셀테크놀로지
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Publication of WO2023128507A1 publication Critical patent/WO2023128507A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a hexameric N-formyl peptide library, and more particularly, to a hexameric N-formyl peptide library for discovering an effective substance for activating a formyl peptide receptor and its use.
  • N-formyl peptide is a peptide derivative in which a formyl group is added to the N-terminus of an amino acid.
  • N-formyl peptides were considered to exist only in proteins produced by bacteria, and were thought to be useful in recognizing foreign substances in the human body and inducing an immune response.
  • N-formyl peptides also exist in proteins produced by mitochondria, and it is no longer thought that they can simply be used to distinguish foreign substances in the human body. Instead, proteins or oligopeptides containing N-formyl peptides appear to come from bacteria or from the mitochondria of damaged tissue, which are pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns, respectively. (DAMP, damage-associated molecular pattern).
  • PAMPs pathogen-associated molecular patterns
  • DAMP damage-associated molecular pattern
  • a representative N-formyl peptide-containing oligopeptide is N-formylmethionine-leucine-phenylalanine (fMLF), which induces/activates immune cells such as neutrophils and monocytes.
  • FPR formyl-peptide receptor
  • GPCRs G Protein-Coupled Receptors
  • FPR mainly includes FPR1, which induces an acute inflammatory response by binding to bacterial-derived peptides, FPR2, which controls inflammatory responses by binding to endogenous ligands such as peptides, proteins, and lipids, and FPR3, whose function is not yet well known.
  • FPR1 which induces an acute inflammatory response by binding to bacterial-derived peptides
  • FPR2 which controls inflammatory responses by binding to endogenous ligands such as peptides, proteins, and lipids
  • the recently known new function of FPR is that when an influx of external substances or infection occurs, a defense mechanism occurs through an acute inflammatory response of innate immunity, and then an inflammatory action occurs, controlling the inflammatory response to an appropriate level and inducing tissue recovery. do. In addition, it induces the removal of apoptotic cells and damaged tissues by macrophages, reduces M1 macrophages that induce inflammatory responses, and increases M2 macrophages
  • Korean Patent Publication No. 2021-0135488 discloses a novel peptide library and a method of using the same.
  • the present invention is to solve various problems, including the above problems, hexamer N- It aims to provide a formyl peptide library and its use. However, these tasks are illustrative, and the scope of the present invention is not limited thereby.
  • any one of X 1 to X 5 excluding the N-terminal formyl methionine is fixed as a specific amino acid, and the rest except for the fixed amino acid is synthesized so that 19 amino acids excluding cysteine are randomly arranged) .
  • the culturing step of treating the peptide library with immune cells and then culturing analyzing the level of formyl peptide receptor activation by recovering the cells that have completed the culturing step, the lysate or medium supernatant of the cells Analysis step: a first selection step of selecting candidate amino acids effective for each fixed position by selecting a peptide pool showing higher activity than the control group in the analysis step; and a second screening step of selecting a candidate group having the highest activity by combining the candidate amino acids.
  • the N-formyl peptide library having the diversity and search efficiency of the present invention made as described above, it is possible to search for active substances of peptides that activate formyl peptide receptors and regulate immune cell inflammatory responses.
  • the N-formyl peptide library can be used to develop formyl peptide pharmacological substances exhibiting efficacy in chronic inflammatory diseases or autoimmune diseases.
  • the scope of the present invention is not limited by these effects.
  • FIG. 1 is a schematic view of the construction of the hexameric N-formyl peptide library of the present invention and the process of searching for effective peptides using the same.
  • Figure 2 is a graph showing the results of analyzing intra-cellular calcium mobilization through FPR1 activation using the hexameric N-formyl peptide library of the present invention.
  • the values in the above graph represent the results of relatively measuring the activity of other peptides with the measured value of the intracellular calcium ion concentration of the peptide having the second amino acid fixed to AA1 in the hexameric N-formyl peptide as 1.
  • Figure 3 is a graph showing the results of analyzing intra-cellular calcium mobilization through FPR2 activation using the hexameric N-formyl peptide library of the present invention.
  • the values in the above graph represent the results of relatively measuring the activity of other peptides with the measured value of the intracellular calcium ion concentration of the peptide having the second amino acid fixed to AA1 in the hexameric N-formyl peptide as 1.
  • FPR formyl-peptide receptor
  • peptide library used in this document is a technology for constructing peptides of various amino acid sequences to be easily searched for, as in finding necessary books in a library.
  • physiologically active substances that can be developed as new biologics can be derived from the diversity of 20 to the 6th power through 120 search processes and subsequent search and verification processes.
  • any one of X 1 to X 5 excluding the N-terminal formyl methionine is fixed as a specific amino acid, and the rest except for the fixed amino acid is synthesized so that 19 amino acids excluding cysteine are randomly arranged) .
  • the C-terminus may be amidated and may be composed of 95 pools according to the fixed amino acids, and may be for formyl peptide receptor (FPR) activation or inflammation response regulating peptide active substance search .
  • FPR formyl peptide receptor
  • the culturing step of treating the peptide library with immune cells and then culturing analyzing the level of formyl peptide receptor activation by recovering the cells that have completed the culturing step, the lysate or medium supernatant of the cells Analysis step: a first selection step of selecting candidate amino acids effective for each fixed position by selecting a peptide pool showing higher activity than the control group in the analysis step; and a second screening step of selecting a candidate group having the highest activity by combining the candidate amino acids.
  • the immune cells include neutrophils, basophils, eosinophils, mast cells, monocytes, macrophages, and dendritic cells.
  • It can be selected from the group consisting of T cells, B cells, and NK cells, and the level of the formyl peptide receptor activation is analyzed by calcium ion permeability analysis, cAMP production analysis, inflammation induction or inflammation relief signal analysis, or immune response analysis.
  • the immune response analysis may be performed by measuring the secretion level of cytokines, chemokines or cytoplasmic granules of immune cells or measuring the phagocytosis of macrophages.
  • FPR formyl peptide receptor
  • M1 pro-inflammatory macrophages
  • M2 anti-inflammatory macrophages
  • Appropriate inflammatory action limits excessive inflammatory response and induces a normal acquired immune response, enabling the ability to respond to repeated inflammatory situations in the future.
  • insufficient inflammatory response can cause chronic inflammation due to continuous inflammatory response and various chronic inflammatory diseases or autoimmune diseases due to abnormal acquired immune response.
  • the inflammatory response induced by FPR does not simply terminate the immune response, but plays a role in helping our body maintain the correct immune system.
  • the resolution of inflammation occurs when various types of anti-inflammatory factors (SPMs, specialized pro-resolving mediators) such as lipids, proteins, and peptides bind to specific receptors of immune cells.
  • SPMs anti-inflammatory factors
  • lipids, proteins, and peptides bind to specific receptors of immune cells.
  • the inventors of the present invention completed the present invention by developing an N-formyl peptide library for discovering an effective substance for activating a formyl peptide receptor in order to discover an effective substance for treating inflammatory diseases (FIG. 1).
  • the N-formyl peptide library of the present invention compensates for the disadvantages of lipid anti-inflammatory factors such as low solubility and stability of lipids and improves inflammation through induction of anti-inflammatory by using synthetic peptides with increased binding force with specific receptors. It can be used to develop new strategies for the development of disease treatments.
  • the present invention relates to a hexameric N-formyl peptide library and is composed of peptides described as formyl-MX 1 X 2 X 3 X 4 X 5 -NH 2 .
  • one amino acid is fixed at each X position, and 20 kinds of amino acids or 19 kinds of amino acids excluding cysteine are randomly arranged at the remaining positions. Therefore, the N-formyl peptide library consists of a pool of 100 to 95 amino acids fixed at each X position.
  • Example 2 Search method for formyl peptide receptor activating active substance from N-formyl peptide through intra-cellular calcium mobilization
  • Formyl peptide receptor (FPR), a type of G protein-coupled receptor (GPCR), induces various intracellular changes, such as changes in calcium ion permeability, when activated by ligand binding. Changes in calcium ion permeability can be measured using a fluorescent substance called Fura-2 AM. As the concentration of calcium ions inside the cell changes, Fura-2 AM shows a change in fluorescence color and changes in the activity of formyl peptides. can be visualized, and the activation of the peptide ligand is confirmed using the digitized fluorescence color change and the efficacy is evaluated by calculating the EC 50 .
  • FPR Formyl peptide receptor
  • GPCR G protein-coupled receptor
  • immune cells such as neutrophils, eosinophils, or macrophages are treated with Fura-2AM and then cultured for several hours.
  • the hydrophobic AM of Fura-2 AM penetrated into the cell is cleaved by the intracellular enzyme and cannot go out of the cell again.
  • the fluorescence change of Fura-2 is measured at 340 nm and 380 nm for several seconds Repeat the measurement at intervals.
  • the change in the ratio of 340 nm/380 nm is calculated using the measured values for each time obtained, and the efficacy of each pool is evaluated through 'maximum value-minimum value'.
  • a sequence is created by combining the selected amino acids, and a change in calcium ion permeability is measured and compared using peptides obtained through synthesis, and the best sequence candidates are selected.
  • the cell line used in this example is a cell line that overexpresses only FPR2 or only FPR1 in cells that do not express FPR1 and FPR2, and FPR2-induced calcium ion concentration change activity (EC 50 for FPR2) was observed using a cell line in which FPR2 was overexpressed. Calcium ion concentration change activity (EC 50 for FPR1) by FPR1 was measured using a cell line in which FPR1 was overexpressed.
  • Example 3 Method for searching formyl peptide receptor activating active substances from N-formyl peptide through cAMP production analysis
  • G protein-coupled receptors mediate cell signaling by activating or inhibiting cAMP production.
  • cAMP Addenosine 3', 5'-cyclic monophosphate, cyclic adenosine monophosphate
  • PKA protein kinase A
  • each peptide pool in which a specific amino acid is fixed at a specific position is treated with immune cells such as neutrophil, eosinophil or macrophage, cultured, and then cell lysate (lysate) is recovered. Then, when alkaline phosphatase-conjugated cAMP and cAMP antibody are added to the lysate and incubated, cAMP and alkaline phosphatase-conjugated cAMP in the lysate competitively bind to the cAMP antibody. At this time, when pNpp substrate is added, it reacts catalytically with alkine phosphatase and turns yellow.
  • the color change in each lysate is measured by optical density (OD) and the cAMP concentration is determined through a colorimetric method that compares with a standard solution of known concentration. quantify it.
  • OD optical density
  • the change of cAMP by the treatment of each peptide pool is compared and evaluated to select amino acids effective for each fixed position. Thereafter, a sequence is generated by combining the selected amino acids, and the cAMP change value is measured and compared using the peptide obtained through synthesis, and the best sequence candidate group is selected.
  • Example 4 Method for searching for effective substances for activating formyl peptide receptors from N-formyl peptides through signal transduction system analysis
  • G protein-coupled receptors Intracellular signaling transmitted through G protein-coupled receptors is largely divided into two representative pathways, one is G-protein mediated signaling and the other is beta-arrestin mediated signaling ( ⁇ -arrestin). arrestin mediated signaling).
  • G protein-coupled receptors can be activated in various ways by multiple ligands, which can activate or inhibit multiple signal transduction systems. At this time, the function of the cell is regulated through a specific signal transduction pathway or a combination thereof.
  • W-peptide W-peptide (WKYMVm) known as a full agonist is known to strongly regulate cAMP, Ca 2+ , MAPK and ⁇ -arrestin.
  • the inflammation-inducing signal regulates only ⁇ -arrestin
  • the anti-inflammatory signal regulates cAMP and Ca 2+ . Therefore, even for formyl peptides that activate the same receptors, their characteristics can be distinguished or inferred through analysis of the sub-signal transduction system. can be selected
  • each peptide pool in which a specific amino acid is fixed at a specific position is treated with immune cells such as neutrophil, eosinophil or macrophage, cultured, and then cell lysate (lysate) is recovered. If necessary, it can be treated with an immune-inducing substance to explore the efficacy of inhibiting the inflammation-inducing signaling system. Thereafter, the lysate was quantified for protein, separated according to size through SDS-PAGE, and changes in various signal transduction systems were analyzed through western blotting, and inflammation induction or anti-inflammatory signals were strongly An inducible peptide pool is selected to select amino acids effective for each fixed position. After that, a sequence is generated by combining the selected amino acids, and the best sequence candidates are selected by analyzing and verifying the signal transduction system using the peptides obtained through synthesis.
  • immune cells such as neutrophil, eosinophil or macrophage
  • Example 5 Method for searching for effective substances for activating formyl peptide receptors from N-formyl peptides through immune response analysis of immune cells
  • Immune cells mediate an inflammatory response by secreting proteins such as cytokines and chemokines out of cells.
  • inflammatory cytokines and chemokines play a role in defending against foreign antigens by triggering an inflammatory response and regulating the innate immune response.
  • an excessive inflammatory reaction that is not properly controlled can cause fever, inflammation, and tissue destruction, which can aggravate the disease itself or the symptoms associated with the disease.
  • TNF ⁇ tumor necrosis factor ⁇
  • IL-6 interleukin 6
  • IL-1 ⁇ interleukin 1 ⁇
  • the inflammation control and anti-inflammatory efficacy of the formyl peptide can be evaluated.
  • a specific amino acid at a specific position in the peptide library constructed in Example 1 of the present invention a specific amino acid at a specific position in the peptide library constructed in Example 1 of the present invention
  • LPS lipopolysaccharide
  • zymosan a specific amino acid at a specific position in the peptide library constructed in Example 1 of the present invention
  • ELISA Enzyme-linked immunosorbent assay
  • cDNA is synthesized using revese transcriptase after RNA extraction using TRIzol from control and peptide-treated cells to measure gene expression. Thereafter, the expression level is quantitatively analyzed in real time using primers of the cytokine or chemokine gene to be analyzed.
  • enzyme-linked immunosorbent assay ELISA
  • the supernatant of the medium is recovered, the medium is put on a plate coated with an antibody that recognizes the cytokine or chemokine to be analyzed, and incubated for several hours so that the antibody can bind well.
  • a substrate is added, and the amount of the corresponding cytokine or chemokine is quantitatively analyzed through a colorimetric method.
  • a peptide pool capable of suppressing cytokine or chemokine secretion of immune cells is selected to select amino acids effective for each fixed position.
  • a sequence is generated by combining the selected amino acids, and a best sequence candidate group is selected using the peptide obtained through synthesis.
  • Example 6 Method for searching for effective substance for activating formyl peptide receptor from N-formyl peptide through granule cell immune response analysis
  • Granulocytes such as basophils, neutrophils, eosinophils, and mast cells, form cytoplasmic granules that contain many inflammatory mediators, such as histamine, heparin, cytokines, chemokines, and several proteases. Involves in the inflammatory response through secretion. Therefore, the degree of activation of granulocytes can be evaluated by measuring tryptase for degranulation.
  • the Tryptase tetrameric serine proteinase
  • each of the peptide pools in which a specific amino acid is fixed at a specific position in the granulocyte cells are treated together and cultured.
  • p-nitroaniline (pNA) is produced by tryptase, and the color development is detected with a spectrophotometer to analyze tryptase activity.
  • pNA p-nitroaniline
  • a peptide pool capable of inhibiting granulocyte degranulation is selected, and amino acids effective for each fixed position are selected.
  • a sequence is generated by combining the selected amino acids, and a best sequence candidate group is selected using the peptides obtained through synthesis.
  • Example 7 Method for searching for effective substances for activating formyl peptide receptors from N-formyl peptides through macrophage immune response analysis
  • phagocytosis Representative immune responses of macrophages are phagocytosis, apoptotic cell recognition, and efferocytosis.
  • the phagocytosis is the main mechanism used to remove pathogens and cell debris, and the ingested material is digested in the phagosome.
  • the apoptotic cell recognition and phagocytosis is a process in which macrophages surround apoptotic cells and absorb large vesicles filled with liquid containing dead cells in a manner similar to macropinocytosis, and the ingested vesicles are phagosomes and They are called efferosomes.
  • apoptotic cell recognition and phagocytosis are known as typical actions of resolution of inflammation by clearing dead immune cells and damaged tissues.
  • each peptide pool in which a specific amino acid is fixed at a specific position in the peptide library constructed in Example 1 is treated together and cultured. Thereafter, the cells are recovered and the macrophages phagocytosing the apoptotic cells are analyzed by flow cytometry (Fluorescence-activated cell sorting) or immunofluorescence.
  • flow cytometry Fluorescence-activated cell sorting
  • amino acids effective for each fixed position are selected.
  • sequences are generated by combining the selected amino acids, and phagocytosis is re-analyzed using peptides obtained through synthesis to select the best sequence candidates.

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Abstract

La présente invention concerne une banque de peptides N-formyle hexamères et ses utilisations, la banque de peptides N-formyle hexamères étant destinée à découvrir une substance active d'activation du récepteur de peptide formyle pour développer un agent thérapeutique pour des maladies inflammatoires à l'aide d'un peptide synthétique ayant une affinité accrue avec un récepteur spécifique.
PCT/KR2022/021294 2021-12-28 2022-12-26 Banque de peptides n-formyl hexamères et ses utilisations WO2023128507A1 (fr)

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KR10-2021-0189771 2021-12-28
KR20210189771 2021-12-28
KR10-2022-0182272 2022-12-22
KR1020220182272A KR20230101718A (ko) 2021-12-28 2022-12-22 육량체 n-포르밀 펩타이드 라이브러리 및 그의 용도

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925529A (en) * 1995-06-07 1999-07-20 The Regents Of The University Of California Method for discovery of peptide agonists
US20030055001A1 (en) * 2001-07-03 2003-03-20 Hyun-Joo Bae Immune-enhancing peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925529A (en) * 1995-06-07 1999-07-20 The Regents Of The University Of California Method for discovery of peptide agonists
US20030055001A1 (en) * 2001-07-03 2003-03-20 Hyun-Joo Bae Immune-enhancing peptides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HE HUI-QIONG, YE RICHARD: "The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition", MOLECULES, vol. 22, no. 3, pages 455, XP093073981, DOI: 10.3390/molecules22030455 *
J. JACOB STROUSE; SUSAN M. YOUNG; HUGH D. MITCHELL; RICHARD D. YE; ERIC R. PROSSNITZ; LARRY A. SKLAR; BRUCE S. EDWARDS: "A novel fluorescent cross‐reactive formylpeptide receptor/formylpeptide receptor‐like 1 hexapeptide ligand", CYTOMETRY A, WILEY-LISS, HOBOKEN, USA, no. 3, 11 November 2008 (2008-11-11), Hoboken, USA, pages 264 - 270, XP072332109, ISSN: 1552-4922, DOI: 10.1002/cyto.a.20670 *
RAABE CARSTEN ALEXANDER; GROPER JIENY; RESCHER URSULA: "Biased perspectives on formyl peptide receptors", BIOCHIMICA ET BIOPHYSICA ACTA, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, vol. 1866, no. 2, 1 January 1900 (1900-01-01), NL , pages 305 - 316, XP085569326, ISSN: 0167-4889, DOI: 10.1016/j.bbamcr.2018.11.015 *

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