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| 1 | Chimeric protein probes for C5a receptors through fusion of the anaphylatoxin C5a core region with a small-molecule antagonist显示文摘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. | 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 | 2019 | Science China Chemistry2019，62，10： | 2 |
| 2 | Low cortisol and risk for PTSD in adult offspring of holocaust survivors显示文摘 | YEHUDA R BIERER L M Schmeidler J | 2000 | Am J Psychiatry2000，157，8： | 2 |
| 3 | Relationship of parental trau-ma exposure and PTSD to PTSD,depressive and anxiety disordersin offspring显示文摘 | Yehuda R Halligan SL Bierer LM | 2001 | J Psychiatr Res2001，35，5： | 1 |
| 4 | Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58显示文摘 | Hahn WC Burakoff SJ Bierer BE | 1993 | J Immunol1993，150，7： | 1 |
| 5 | The effect of desferrithiocin,an oral iron chelator,on T-cell function显示文摘 | Bierer BE Nathan DG | 1990 | Blood1990，76，10： | 1 |
| 6 | CD28/CTLA4 and CD80/CD86 fignalies:signaling and ruction 显示文摘 | Slavik JM Hutchcroft JE Bierer BE | 1999 | Immunol Res1999，19，： | 1 |
| 7 | Relationship of Parental Trauma Exposure and FISD to FISD, Depressive and Anxiety Disorders in Offspring 显示文摘 | Yehuda Rashel Halligan Sarah L Bierer Linda M | 2001 | Journal of Psychiatric Research (2001)2001，，： | 1 |
| 8 | Continuous renal replacement therapy in critically ill patients : monitoring circuit function 显示文摘 | Holt AW Bierer P Bersten AD | 1996 | Anaesth Intensive Care1996，24，4： | 1 |
| 9 | Calcineurin phosphatase activity in T lymphocytes is inhibited by FK506 and cyclosporin A显示文摘 | Fruman DA Klee CB Bierer BE | 1992 | Proc Natl Acad Sci USA1992，89，： | 1 |
| 10 | CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28显示文摘 | SLAVIK J M FIUTCHCROFT J E BIERER B E | 1999 | J Biol Chem1999，274，5： | 1 |
| 11 | Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring 显示文摘 | YEHUDA R HALLIGAN S L BIERER L M | 2001 | J Psychiatr Res2001，35，5： | 1 |
| 12 | Comparative absorption and transport of five common carotenoids in preruminant calves显示文摘 | Bierer T L Merchen N R Erdman J W | 1995 | The Journal of Nutrition1995，125，6： | 1 |
| 13 | Antihyperglycemic activities of cryptolepine analogues:An ethnobotanical lead structure Isolated from cryptolepis sanguinolenta显示文摘 | Donald E Bierer Larisa G Dubenko Pingsheng Zh-ang | 1998 | J Med Chem1998，41，： | 1 |
| 14 | Low cortisol and risk for PTSD in adult offspring of holocaust surviors显示文摘 | Yehuda R Bierer LM Schmeidler | 2000 | Am J Psychiatry2000，157，： | 1 |
| 15 | Pre-treatment global quality of health predicts progression free survival in metastatic kidney cancer patients treated with sorafenib or sunitinib显示文摘 | Edwin H Gerss J Bierer S | 2009 | J Cancer Res Clin Oncol2009，135，1： | 1 |
| 16 | Cardiopulmonary exercise testing in Fabry disease显示文摘 | Bierer G Kamangar N Balfe D | 2005 | Respiration2005，72，5： | 1 |
| 17 | Calcineurin phosphatase activity in T lymphocytes is inhibited by Fk506 and cyclosporin A 显示文摘 | Fruman DA Klee CB Bierer BE | 1992 | Proc Natl Acad Sci USA1992，89，9： | 1 |
| 18 | Identification of novel targets of immunosuppressive agents by cDNA-based microarray analysis显示文摘 | Cristillo A D Bierer B E | 2002 | J Biol Chem2002，277，： | 1 |
| 19 | EB1 proteins regulate microtubule dynamics,cell polarity,and chromosome stability显示文摘 | Tirnauer JS Bierer BE | 2000 | J Cell Bio2000，149，4： | 1 |
| 20 | Calcineurin Phosphatase Activity in T lymphocytes is Inhibited by FK 506 and Cyclosporin A显示文摘 | D A FRUMAN C B KLEE B E BIERER | 1992 | Pro Nation Academy Sci USA1992，89，9： | 1 |
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