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chimeric protein probes for c5a receptors through fusion of the anaphylatoxin c5a core region with a small-molecule antagonist

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Science china chemistry 2019年第10期62卷 1371-1378页

作者： chao Zuo Wei-Wei Shi Xiao-Xu chen Marie Glatz Bernd Riedl Ingo Flamme Elisabeth Pook Jiawei Wang Ge-Min Fang Donald Bierer Lei Liu Tsinghua-Peking center for Life Sciences Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyCenter for Synthetic and Systems BiologyDepartment of ChemistryTsinghua UniversityBeijing 100084China School of Life Science Institutes of Physical Science and Information TechnologyAnhui UniversityHefei 230601China Bayer AG Department of Medicinal ChemistryAprather Weg 18A42096 WuppertalGermany Bayer AG Cardiovascular Research42096 WuppertalGermany Bayer AG Lead Discovery42096 WuppertalGermany

Blockade of the interaction of anaphylatoxin c5a with its receptor c5aR1 has been actively studied as a potential treatment for many inflammatory diseases;but current c5a antagonists exhibit inadequate potency and poor species cross-reactivity, and novel biochemical tools are needed to investigate whether the core region of c5a contains important interaction epitopes that can explain these limitations. Herein, we report the development of chimeric protein c5a probes containing both the complete core region of rat or human c5a, and the small-molecule antagonist PMX53-1. These probes were chemically synthesized through hydrazide-based native chemical ligation of a linear peptide hydrazide with the requisite cyclopeptidic antagonist, both of which were made by solid-phase synthesis. Quasi-racemic X-ray crystallography established that attachment of PMX53-1 did not affect the structure of the core region of c5a. Subsequent c5aR1 activity assays demonstrated the probes can provide valuable insights into the development of c5a antagonists;for example, they exhibited significantly better binding affinity and much improved species cross-reactivity than PMX53-1, supporting the notion that the effect of some epitopes outside the c-terminus of c5a should be taken into consideration when designing better c5a antagonists. Surprisingly, the core region of c5a was found to partially agonize c5aR1, suggesting the presence of more than one agonistic interaction in the binding of c5a to c5aR1. This study exemplifies the value of chemical protein synthesis in developing novel receptor probes for drug discovery research.

关键词： anaphylatoxin c5a PMX53 quasi-racemic X-ray crystallography native chemical ligation

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The role of complement c5a receptor in DPSc odontoblastic differentiation and in vivo reparative dentin formation

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International Journal of Oral Science 2022年第1期14卷 71-79页

作者： Muhammad Irfan Ji-Hyun Kim Hassan Marzban David AReed Anne George Lyndon Fcooper Seung chung Department of Oral Biology University of Illinois at ChicagoChicagoUSA Department of Human Anatomy and cell Science University of ManitobaWinnipegCanada

Therapeutic dentin regeneration remains difficult to achieve,and a majority of the attention has been given to anabolic strategies to promote dentinogenesis directly,whereas,the available literature is insufficient to understand the role of inflammation and inflammatory complement system on *** aim of this study is to determine the role of complement c5a receptor(c5aR)in regulating dental pulp stem cells(DPScs)differentiation and in vivo dentin *** DPScs were subjected to odontogenic differentiation in osteogenic media treated with the c5aR agonist and c5aR *** vivo dentin formation was evaluated using the dentin injury/pulp-capping model of the c5a-deficient and wildtype *** vitro results demonstrate that c5aR inhibition caused a substantial reduction in odontogenic DPScs differentiation markers such as DMP-1 and DSPP,while the c5aR activation increased these key odontogenic genes compared to control.A reparative dentin formation using the c5a-deficient mice shows that dentin regeneration is significantly reduced in the c5a-deficient *** data suggest a positive role of c5aR in the odontogenic DPScs differentiation and tertiary/reparative dentin *** study addresses a novel regulatory pathway and a therapeutic approach for improving the efficiency of dentin regeneration in affected teeth.

关键词： c5a vivo inflammation

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chemical synthesis and racemic crystallization of rat c5a-desArg

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chinese chemical Letters 2020年第3期31卷 693-696页

作者： chao Zuo Baochang Zhang Meng Wu Donald Bierer Jing Shi Ge-Min Fang School of Life Science Institutes of Physical Science and InformationTechnologyAnhui UniversityHefei 230601China Department of chemistry Tsinghua UniversityBeijing 100084China Department of chemistry University of Science and Technology of ChinaHefei 230601China Bayer AG Department of Medicinal ChemistryAprather Weg 18A42096WuppertalGermany

The deletion of the c-terminal arginine of the anaphylatoxin protein c5a reduces it receptor binding *** how c-terminal arginine affects the structure and bioactivity of c5a is important for the development of c5a c-terminal mimics as drug ***,we report the total chemical synthesis of rat c5a and its D-enantiomer with its c-terminal arginine deleted,namely L-rc5a-desArg and *** structure of rc5a-desArg was then determined by racemic crystallography for the first *** c-terminal residues of rc5a-Arg were found to expand from the fourth helix in a continuous helical confo *** c-terminal conformation is significantly different from that of the previously reported full-length of c5a,indicating that the deletion of c-terminal arginine residue could result in the destruction of a positively charged surface formed by two adjacent Arg residues in c5a.

关键词： Anaphylatoxin c5a Racemic crystallization Solid phase peptide synthesis chemical protein synthesis Hydrazide-based native chemical ligation

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Mechanism of c5a-induced immunologic derangement in sepsis

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cellular & Molecular Immunology 2017年第9期14卷 792-793页

作者： Ruonan Xu Fang Lin chunmei Bao Fu-Sheng Wang Treatment and Research centre for Infectious Disease Beijing 100039China The Institute of Intensive care Unit Beijing 100039China The Institute of clinical Examination centre Beijing 100039China

Sepsis is a life-threatening medical condition that triggers an uncontrolled inflammatory reaction and is caused by the entry of various microorganisms into the human *** is mainly encountered in intensive care units(IcUs)due to the reduced immunological defenses of IcU *** 1.5 million patients develop sepsis annually in industrialized countries.

关键词： annually c5a ang

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Role of c5a-c5aR axis in the development of atherosclerosis

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Science china(Life Sciences) 2014年第8期57卷 790-794页

作者： AN GuiPeng REN GuoRui AN FengShuang ZHANG cheng Key Laboratory of cardiovascular Remodeling and Function Research Ministry of Education and Ministry of HealthShandong University Qilu Hospital Department of cardiology Shandong University Qilu Hospital Department of Geriatrics Qingdao Municipal Hospital

complement component 5a(c5a)is a 74 amino acid glycoprotein and an important proinflammatory mediator that is cleaved enzymatically from its precursor,c5,on activation of the complement cascade.c5a is quickly metabolised by carboxypeptidases,forming the less-potent c5a desArg.c5a and c5a desArg interact with their receptors(c5aR and c5L2),which results in a number of effects which are essential to the immune response.c5a has a broad range of biological effects throughout the human body because the widespread expression of c5a receptors throughout the human organs enables c5a and c5a desArg to elicit a broad range of biological ***,accumulating evidence in humans and experimental animal models shows that the c5a-c5aR axis is involved in the development of atherosclerosis *** absence or blockade of c5aRs greatly reduces the formation of atherosclerotic lesions or wire-injury-induced neointima formation in atherosclerosis-prone *** c5a level was related to the major adverse cardiovascular events in patients with advanced atherosclerosis and those with drug-eluting stent ***,the c5a-c5aR axis may be a significant pathogenic driver of arteriosclerotic vascular disease,making c5a-c5aR inhibition an attractive therapeutic strategy.

关键词： c5a c5a receptors atherosclerosis

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Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the c5a receptor

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cellular & Molecular Immunology 2016年第5期13卷 651-657页

作者： Jessy J. Alexander Lee D. chaves Anthony chang Shruti Dighe Alexander Jacob Richard J. Quigg Division of Nephrology Department of Medicine University at Buffalo School of Medicine and Health Sciences Buffalo NY USA Department of Pathology The University of Chicago Chicago IL USA Correspondence: Dr Jessy J. Alexander Division of Nephrology State University of New York at Buffalo Clinical and Translational Research Center 875 Ellicott Street 8-022 Buffalo NY 14203 USA

Activation of complement generates c5a which leads to signaling through c5aR 1. This is tightly controlled, including by the plasma proteins factor H （FH） and carboxypeptidase N. Here we studied a chronic serum sickness （cSS） model of glomerulonephritis （GN） in which there is an active humoral immune response, formation of glomerular immune complexes （Ics）, and resulting glomerular inflammation. The antibody response, glomerular Ic deposition, the degree of GN, and consequent renal functional insufficiency in cSS were all worse in FH-/- mice compared to wild-type FH＋/＋ animals. This was ameliorated in the former by giving a c5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking cP-mediated inactivation of c5a increased these disease measures. Thus, complement regulation by both plasma FH and cP to limit the quantity of active c5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through c5aR1 enhances the humoral immune response as well as the inflammatory response to Ics that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of c5a in Ic-mediated GN has potential clinical relevance.

关键词： c5a carboxypeptidase N factor H glomerulonephritis

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calpain裂解Atg5决定中性粒细胞发生自噬还是凋亡，以及c5a在其中的可能作用

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生物化学与生物物理进展 2008年第12期35卷 1358-1363页

作者：张保全郭振辉房巍吕凤林第三军医大学大坪医院野战外科研究所创伤烧伤与复合伤国家重点实验室重庆400042 广州军区总医院MIcU科广州510010

通过阐明c5a、calpain和Atg5相互作用,为开展新的研究寻找方向.中性粒细胞凋亡控制炎症反应及其强度,多种疾病和中性粒细胞凋亡失调有关,但其发生机制尚未阐明.c5a为补体片段,有多种功能,如诱导中性粒细胞趋化、呼吸爆发、增强吞噬、颗... 详细信息

通过阐明c5a、calpain和Atg5相互作用,为开展新的研究寻找方向.中性粒细胞凋亡控制炎症反应及其强度,多种疾病和中性粒细胞凋亡失调有关,但其发生机制尚未阐明.c5a为补体片段,有多种功能,如诱导中性粒细胞趋化、呼吸爆发、增强吞噬、颗粒酶释放和延迟凋亡.已知calpain涉及中性粒细胞功能及凋亡调节并对该凋亡发生具有特异性.不同刺激因素可通过不同路径调节不同calpain亚型的活性.已有报道c5a可以通过调节calpain亚型活性而调节中性粒细胞的趋化反应.另外,自噬是真核细胞中广泛存在的生物过程,具有细胞保护作用,Atg5对于自噬体形成必不可少.calpain可裂解Atg5为24kutAtg5,使其失去形成自噬体的功能并介导凋亡.Atg5参与了自噬和凋亡的转换.

关键词：中性粒细胞凋亡自噬 Atg5 calpain c5a

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Effect of anaphylatoxin c3a, c5a on the tubular epithelial-myofibroblast transdifferentiation in vitro

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chinese Medical Journal 2011年第23期124卷 4039-4045页

作者： LIU Fang GOU Rong HUANG Jun FU Ping cHEN Feng FAN Wen-xing HUANG You-qun ZANG Li WU Min QIU Hong-yu WEI Da-peng Division of Nephrology West China Hospital of Sichuan University Chengdu Sichuan 610041 China

Background Tubulointerstitial renal fibrosis is the common end point of progressive kidney diseases, and tubular epithelial-myofibroblast transdifferentiation （TEMT） plays a key role in the progress of tubulointerstitial renal fibrosis. Anaphylatoxin c3a and c5a are identified as novel profibrotic factors in renal disease and as potential new therapeutic targets. The aim of this study was to investigate whether c3a, c5a can regulate TEMT by transforming growth factor-β1 （TGF-β1）/connective tissue growth factor （cTGF） signaling pathway and the effects of c3a and c5a receptor antagonists （c3aRA and c5aRA） on c3α- and c5α-induced TEMT. Methods HK-2 cells were divided into c3a and c5a groups which were subdivided into four subgroups： control group, 10 ng/ml TGF-I31 group, 50 nmol/L c3a group, 50 nmol/L c3a plus 1 pmol/L c3aRA group; control group, 10 ng/ml TGF-I^I group, 50 nmol/L c5a group, 50 nmol/L c5a plus 2.5 pmol/L c5aRA group. TGF-β1 receptor antagonist （TGF-β1 RA） 10 IJg/ml was used to investigate the mechanism of c3α- and c5α-induced TEMT. Electron microscopy was used to observe the morphological changes. Immunocytochemistry staining, real-time PcR and Western blotting were used to detect the expressions of a smooth muscle actin （α-SMA）, E-cadherin, col-I, c3a receptor （c3aR）, c5aR, cTGF and TGF-β1. Results HK-2 cells cultured with c3a and c5a for 72 hours exhibited strong staining of α-SMA, lost the positive staining of E-cadherin, and showed a slightly spindle-like shape and loss of microvilli on the cell surface. The expressions of α-SMA, E-cadherin, col-I, c3aR, c5aR, TGF-β1 and cTGF in c3α- and c5α-treated groups were higher than normal control group （P 〈0.05）. c3aRA and c5aRA inhibited the expressions of α-SMA, col-I, c3aR, c5aR, and up-regulated the expression of E-cadherin （P 〈0.05）. TGF-β1 and cTGF mRNA expressions induced by c3a and c5a were partly blocked by TGF-β1 RA （P 〈0.05）. conclusion c3a and c5a can induce TEMT via the up-regulations of c3aR an

关键词： c3a c5a tubular epithelial-myofibroblast transdifferentiation transforming growth factor-ill connective tissue growth factor

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草鱼c5a、c5aR和FⅡ多克隆抗体的制备与表达特性

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水产学报 2022年第5期46卷 785-796页

作者：苏杭肖调义许宝红刘巧林吕丽刚刘益湖南农业大学湖南省特色水产资源利用工程技术研究中心

为研究草鱼补体蛋白5a (complement component 5a,c5a)、补体蛋白5a受体(c5a receptor,c5aR)和凝血因子Ⅱ(blood coagulation factorⅡ，FⅡ)在感染草鱼呼肠孤病毒(grass carp reovirus,GcRV)时的蛋白表达和相互作用，针对草鱼c5a和FⅡ蛋白构建了原核表达体系、针对草鱼c5aR蛋白构建c5aR-KLH偶联物，纯化蛋白，免疫日本大耳白兔制备3种蛋白的多克隆抗体。用蛋白质印迹(Western blot)、免疫共沉淀(co-IP)和拉下(pull down)实验检测3种蛋白表达与互作关系，Western blot结果显示，c5a和c5aR在健康草鱼的肝脏、脾脏、肾脏、头肾、肠、鳃和肌肉中均有蛋白表达，FⅡ在肝脏、脾脏和肠中表达，而在肾脏、头肾、鳃和肌肉中不表达；在感染GcRV的草鱼肝脏组织中c5a、c5aR和FⅡ蛋白均随病程进展呈现上升趋势。co-IP结果显示，在GcRV处理后，c5a、c5aR和FⅡ蛋白具有相互作用关系。pull down结果显示，c5a pull down共鉴定得到c3、RIG-I等28种候选蛋白，c5aR pull down共鉴定得到转醛醇酶、巨球蛋白等24种候选蛋白。该研究为深入探讨c5a、c5aR和FⅡ互作调控关系以及进一步探索补体和凝血级联系统中3个关联蛋白响应GcRV感染的作用机制奠定了基础。

关键词：草鱼 c5a c5aR FⅡ 多克隆抗体草鱼呼肠孤病毒(GcRV) 表达特性

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c5a对内皮细胞表达血栓调节蛋白的影响

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中国危重病急救医学 2009年第3期21卷 168-171页

作者：房巍郭振辉张保全吴晓凤李平吕凤林苏磊广州医学院广东 510010 广州军区广州总医院急危重病中心广东 510010 第三军医大学附属大坪医院野战外科研究所一室重庆400042

目的探讨补体c5a对人脐静脉内皮细胞（HUVEcs）血栓调节蛋白（TM）表达的影响。方法体外培养HUVEcs，以终浓度200μg／L重组人c5a刺激HUVEcs8、12、16、20h以及以终浓度100、200、300μg／L的c5a刺激HUVEcs 12h，采用实时荧光定量聚合... 详细信息

目的探讨补体c5a对人脐静脉内皮细胞（HUVEcs）血栓调节蛋白（TM）表达的影响。方法体外培养HUVEcs，以终浓度200μg／L重组人c5a刺激HUVEcs8、12、16、20h以及以终浓度100、200、300μg／L的c5a刺激HUVEcs 12h，采用实时荧光定量聚合酶链反应（PcR）、蛋白质免疫印迹法（Western blotting）分别检测TM的mRNA及蛋白表达变化；观察c5a对其表达TM的时－效和量－效关系。结果c5a抑制了HUVEcs在TM的mRNA和细胞膜表面蛋白水平表达。同时，c5a对TM表达的抑制作用存在时一效关系[8、12、16、20h时蛋白为（93．11±1．57）×10^-2、（71．05±3．39）×10^-2、（65．48±4．28）×10^-2、（62．69±4．03）×10^-2，mRNA为（301．71±80．40）×10^-6（38．29±20．24）×10^-6、（8．82±2．66）×10^-6、（7．05±0．80）×10^-6]，且均于12h后降低程度明显减缓（P均〈0．05）；并存在量-效关系（c5a100、200、300mg／L时蛋白为（113．25±3．97）×10、（80．18±2．56）×10、（73．22±4．36）X10，mRNA为（401．77±20．46）×10、（31．12±3．51）×10^-6、（18．19±1．46）×10^-6]，TM蛋白在c5a300μg／L、mRNA在c5a200μg／L时刺激12h降低程度明显减缓（P均〈0．05）。结论c5a通过抑制TM的结构基因表达，进而减弱TM的蛋白翻译，从而参与了脓毒症时凝血亢进、炎症损害的病理生理过程。

关键词： c5a 内皮细胞血栓调节蛋白

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