Cyclophilin inhibitors

Flisiak R, Dumont J-M, Crabbe R. (2007) Cyclophilin inhibitors in hepatitis C viral infection. Expert Opin Invest Drugs 16 1345-1354. 

Ma S, Boemer JE, TiongYip C, Weidmann B, Ryder NS, Cooreman MR Lin K. (2006) NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 50 2976-2982. 

Inhibitor 1, inhibitor 2 DARPP-32, NIPP1 Inhibitor 12A, inhibitor 22A Immunophilins Cyclosporin A-cyclophilin, FK06-FK506-binding protein... 

In cyclophilin inhibition assays (Table 1), a comparison of the fluoroolefin and olefin isosteres illustrated the subtle differences between the two closely related isosteres and thereby presumably the importance of the added electrostatic and electronic interactions derived from fluorination. Note in particular that the c/s 1 (H) disastereomer was a more potent inhibitor than the cis 1 (F) and that similarly trans 2 (F) was more effective than trans 2 (H). 

H.C. Wang, K. Kim, R. Bakhtiar, J.P. Germanas, Structure-activity studies of ground-and transition-state analogue inhibitors of cyclophilin, J. Med. Chem. 44 (2001) 2593-2600. 

Figure 16 (a) The structure of calcmeurin with suhunit A in cyan. The catalytic site containing a Zn-Fe hinding site is in dark red. Subunit B in orange contains four calciimi (green) ions hound to the EF-hand motifs. Both N- and C-terminal domains of calcineurin B interact to the same extended a-helix of calcineurin A. (h) The inhibitor complex cyclosporin A (red) and cyclophilin (violet) interacts with both calcineurin subunits and blocks the catal)dic site of calcineurin ... 

Cyclosporine binds to an intracellular protein, cyclophilin. Cyclophilins and similar binding proteins are now referred to collectively as immunophilins and their enzymatic activities are relevant to the actions of immunosuppressants such as cyclosporine and tacrolimus. This complex inhibits the phosphatase activity of calcineurin, which in turn prevents dephosphorylation and translocation of NFAT. NFAT is required to induce a number of cytokine genes, including that for interleukin-2, which serves as a T-cell growth and differentiation factor (Krensky et al., 2005 Matsuda and Koyasu, 2000). Cyclosporine also increases expression of TGF-p, which is a potent inhibitor of IL-2 stimulated cell proliferation and generation of cytotoxic T lymphocytes (Khanna et al., 1994). 

For the preparation of Gly- j/-[CF=CH]-Pro in relation to the study of cyclophilin A inhibitors, Welch and co-workers employed the Peterson reaction of a-fluoro-a-trimethylsilyl acetate (15a,b) with ketone 10. E/Z selectivity was found to be influenced by the ester part of the acetate (see Scheme 10.4) [15]. The reaction of tert-butyl ester 15a gave almost an equal amount of the isomers (lib, E Z= 1 1.1), while moderate E selectivity was observed when trimethylphenyl ester 15b was used (11c, E Z= 6 1). Conversion of ester Z-llb to amino derivative 16 was achieved via the Mitsunobu reaction of phthalimide with the alcohol formed by the DIBAL-H reduction of Z-llb. 

Among the plethora of NMR and crystallographic structures available in the Broo-khaven Protein Data Bank, most concern either cyclophilin alone or assodated with various substrates and effectors (81 structures). FKBP structures have essentially been resolved alone or bound to their effectors, including inhibitors (45 structures including MIP). Pinl, Par 14, and ESS1 (respectively 8, 4, and 1 structures) and the trigger factor (7 structures) are also represented [12]. 

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