Cyclophilin inhibitors as antiviral agents

Abstract

Cyclophilins (Cyps) are ubiquitous proteins that effect the cis-trans isomerization of Pro amide bonds, and are thus crucial to protein folding. CypA is the most prevalent of the ~19 human Cyps, and plays a crucial role in viral infectivity, most notably for HIV-1 and HCV. Cyclophilins have been shown to play key roles in effective replication of a number of viruses from different families. A drug template for CypA inhibition is cyclosporine A (CsA), a cyclic undecapeptide that simultaneously binds to both CypA and the Ca(2+)-dependent phosphatase calcineurin (CN), and can attenuate immune responses. Synthetic modifications of the CsA scaffold allows for selective binding to CypA and CN separately, thus providing access to novel, non-immunosuppressive antiviral agents.

Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes

“…SCY-635 and Alisporivir together with NIM811 are now considered as the most advanced of all host-targeted antiviral agents [56][57][58]. A great deal of work describing the results of clinical trial using nonimmunosuppressive NIM811, SCY-635 and Alisporivir against HCV infection and anti viral effects of other CsA derivatives has recently been summarized elsewhere [59,60].…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…CypA inhibitors such as cyclosporine A (CsA) have been shown to inhibit the replication of HIV, HCV, influenza virus, CoV, HBV, HSV, human cytomegalovirus (HCMV), VSV, vaccinia virus (VV) and human papillomavirus (HPV) [105][106][107][108][109][110][111][112][113][114] . Alisporivir (Debio-025) and SCY-635, both CsA analogues, have shown antiviral activity against HCV in vivo and are currently in combination with other anti-HCV compounds in various clinical trials 115,116 . ER α-glucosidases I and II play a critical role in glycosylation of viral proteins 102 .…”

“…Therefore, derivatives of CsA have been prepared by semisynthesis that are devoid of calcineurin activity, but maintain the cyclophilin inhibition. The most advanced congeners are alisporivir (or DEB025) (7) and SCY-635 (8) 116 . Although virus mutations that confer resistance to alisporivir have been reported 109,110 , a synergistic effect when used in combination with anti-HCV DAAs has been noted 156 and the drug is in clinical trials for the treatment of HCV infection 69 .…”

Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance

“…As a result, T-cell activation is suppressed (Liu et al, 1991). As a protein chaperone with peptidyl-prolyl cis-trans isomerase activity, CypA has been involved in the replication of multiple viruses and represents a host factor for therapeutic intervention (Lin and Gallay, 2013; Peel and Scribner, 2013b; Sweeney et al, 2014). Re-design of CsA ( 1 ) has produced a number of non-immunosuppressive antiviral candidates in clinical trials, such as Alisporivir (Debio-025) and SCY-635 for HCV infection and NIM818 for HIV infection (Peel and Scribner, 2013b).…”

“…As a protein chaperone with peptidyl-prolyl cis-trans isomerase activity, CypA has been involved in the replication of multiple viruses and represents a host factor for therapeutic intervention (Lin and Gallay, 2013; Peel and Scribner, 2013b; Sweeney et al, 2014). Re-design of CsA ( 1 ) has produced a number of non-immunosuppressive antiviral candidates in clinical trials, such as Alisporivir (Debio-025) and SCY-635 for HCV infection and NIM818 for HIV infection (Peel and Scribner, 2013b). Due to its promising antiviral efficacy, CsA ( 1 ) was also investigated in inhibiting influenza A virus replication and was found to inhibit two influenza A strains, A/WSN/33 (H1N1) and A/Puerto Rico/8/34 (H1N1), with low micromolar EC 50 values (Hamamoto et al, 2013a; Liu et al, 2012).…”