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.
Cyclophilins are members of the Propyl Peptidase Isomerase (PPIase) family of proteins and have recently been found to be required for efficient replication and/or infectivity of several viruses. Cyclosporine A (CsA), the prototypical inhibitor of cyclophilins has shown good activity against several key viruses, including HIV‐1 and HCV, however the immunosuppressive activity of CsA precludes its use as an effective anti‐viral agent. Structural information derived from the ternary complex formed by CsA, cyclophilin A and calcineurin has allowed the design of non‐immunosuppressive derivatives of CsA that retain, and in some cases improve, antiviral activity toward hepatitis C. Chemical modification of CsA has led to compounds with improved pharmacokinetic properties and with reduced drug‐drug interaction potential. Non‐CsA derived inhibitors of cyclophilin A have recently been identified and hold promise as synthetically more tractable leads for cyclophilin‐based discovery projects.
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
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