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Speaker ： Geng Hao Supervisor ： Prof. Yun-Dong Wu Nov.22th 2013

Group Meeting Literature Report . Brief Introduction on Mechanism of Cyclosporin. Speaker ： Geng Hao Supervisor ： Prof. Yun-Dong Wu Nov.22th 2013. Outline. The Discovery of Cyclosporin A and Cyclophilin Calcineurin and CsA-CyP complex

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Speaker ： Geng Hao Supervisor ： Prof. Yun-Dong Wu Nov.22th 2013

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  1. Group Meeting LiteratureReport Brief Introduction on Mechanism of Cyclosporin Speaker ：GengHao Supervisor：Prof. Yun-Dong Wu Nov.22th 2013

  2. Outline • The Discovery of CyclosporinA and Cyclophilin • Calcineurin and CsA-CyP complex • The mechanism of immunosuppressant-CsA • Cyclosporinanalogs

  3. The Discovery of Cyclosporin A CyclosporinA (often shortened to CsA) was initially isolated from the fungus Tolypocladium inflatum (多孔木霉), found in a soil sample obtained in 1969 from MountainHardangervidda, Norway by Dr. Hans Peter Frey, a Sandoz biologist. CyclosporinA Mountain Hardangervidda(哈当厄高原) No antibacterialactivity. The immunosuppressive effect of cyclosporinwas discovered on 31 January 1972 by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin, M.D. Tolypocladium inflatum (多孔木霉) Svarstad, 2000,From Norway to Novartis: Cyclosporin from Tolypocladium inflatum in an open access bioprospectingregime. Biodiversity and Conservation9 (11): 1521–1541.

  4. The Discovery of Cyclosporin A Most peptides are synthesized by ribosomes, but cyclosporin is a cyclic nonribosomal peptide of 11 amino acids. 7 N-Methylations 3 uncommon amino acid (contains a single D-amino acid)at 1, 2, 8 position respectively Very famous immunosuppresant! The first patient, on 9 March 1980, was a 28-year-old woman. Cyclosporinwas subsequently approved for use in 1983. Since then, it has been used to prevent and treat graft-versus-host reactions in bone-marrow transplantation and to prevent rejection of kidney, heart, and liver transplants. And it raised the survival rate from 50% to 70% after internal organ transplants. BorelJF, 2002. History of the discovery of cyclosporin and of its early pharmacological development.Wien. Klin. Wochenschr.114 (12): 433–7

  5. The Discovery of Cyclophilin What’s the target of CsA ? 1984 1991 1993

  6. The Discovery of Cyclophilin Cyclophilins(Cyp) are a family of proteins that bind to cyclosporine. Originally discovered as a specific ligand of Cyclosporin and named based on this. CypA is the most famous one which has a beta barrel structure with two alpha helices and a beta-sheet. Cyclophilin is not born to bind to CsA Cyclophilin A is a cytosolic and abundant protein (0.1% of total cellular protein). Possesses a peptidylprolylisomerase(PPIase) activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding. Has been proposed to act as a chaperone(分子伴侣) in protein trafficking. Play important role for some virus replication.(HIV,HCV) WatashiK, et a1. ,2003, 38:1282-1288 Fischer G, Aumuller T; Rev PhysiolBiochemPharmaeol, 2003, 148: 105—150

  7. Calcineurin and CsA-CyP complex What happened after CsA bind to Cyclophilin A ? 1984 2002

  8. The mechanism of immunosuppressant-CsA Calcineurin (CN) is a enzyme involved in the T-cell activation. Known as calcium-dependent serine-threonine phosphatase, Calcineurin activates nuclear factor of activated T cell(NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. interleukin 2 Majed M. Hamawy, et al .Transplantation Review, 2003, 17, 165-171

  9. The mechanism of immunosuppressant-CsA Cyclosporine (CsA) binds to cyclophylin (CpN), forming a complex. The CsA–CpN complex binds and blocks the function of the enzyme calcineurin (CaN), As a result, CaN fails to dephosphorylate the nuclear factor of activated T cells (NF-ATc), and thereby blocks the transport of NF-ATc to the nucleus and the binding of NF-ATc to the its partner(NF-ATn). No complexbind to the promoter of the interleukin 2 (IL-2) gene and initiate IL-2 production. Consequently, T cells do not produce IL-2, which is necessary for full T-cell activation. Therefore the CsA inhibits T cell activation. Expression of IL-2 et al cell factor Proliferation and differentiation of T cell T Cell activation CsA-CypA complex Steffan Ho, et al. Clinical Immunology and immunopathogy, 1996, 80, 40-45

  10. The mechanism of immunosuppressant-CsA Cyclophilin A(CypA) binding domain Calcineurin binding domain Qing Huai, HengmingKe;PNAS, 2002, 99, 12037-12042

  11. The mechanism of immunosuppressant-CsA The CyPA-CsA-CN structure revealed many hydrogen bond and hydrophobic interactions between CypA-CsA complex and CN.CyPA-CsA interacts with Arg-122 at the active site of CN, implying direct involvement of CyPA-CsA in the regulation of CN catalysis. Interfacial interactions between CN and CsA-CyP. A total of 25 residues of CN are involved in interaction with CyPA-CsA. Red balls represent residues interacting with CyPA and green balls represent residues interacting with CsA (green sticks). Qing Huai, HengmingKe;PNAS, 2002, 99, 12037-12042

  12. Crystal structure of Cyclosporin A 1984 HR Loosli, H Kessler, H Oschkina,; HELV CHIM ACTA, 1985, 68, 682-704

  13. Crystal structure of CsAand stucture when binding with Cyclophilin Amide nitrogen toward the inside direction N-methylation toward the outside Beneficial to pass through the membrane Conformation of CsA in 1MF8 Overlay of Crystal structure of CsA from different CsA-CyP complexes No intermolecular H-bond

  14. Calcineurin and CsA-CyP complex x

  15. Non-Immunosuppressive Cyclosporin Analogs Cyclosporin A DEBIO-025 SCY-635 NIM-811

  16. Non-Immunosuppressive Cyclosporin Analogs NIM 811 Inhibition of Human Immunodeficiency VirusType1 Replication by SDZ NIM 811 , a NonimmunosuppressiveCyclosporine Analog. ANTIMICROBLAL AGENTS AND CHEMOTHERAPY,Aug. 1994,p. 1763-1772 Debio-025 In vitro blood distribution and protein binding of a new anti-HIV drug, DEBIO-025. DRUG METABOLISM REVIEWS,2005, 37, p.29-29 SCY-635 Preclinical evaluation of SCY-635, a cyclophilin inhibitor with potent anti-HCV activity.HEPATOLOGY, 2006,44,p.534-535 Gallay PA, Clin. Liver Dis., 2009

  17. Whatare weinterested in • The effect of different substituents on the conformation of Cyclosporin • How the conformation affect the binding of Cyclosporin and Cyclophilin /CsA-CyP-Calcinurin • Design new modification for better different kinds of activities. First step : A good computational method to study it.

  18. Preview Cyclophilin What are the different roles they play. How CypA bound to HIV-1 Capsid Anti-HCV Mechanisms of CypA Welcome to the next literature report!

  19. Thank you for your attention!

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