Cyclophilin Inhibitors

Vuagniaux, Grégoire; Hamel, Arnaud; Crabbé, R.; Porchet, Hervé; Dumont, Jean-Maurice

doi:10.1002/9783527635955.ch7

Cited by 1 publication

(1 citation statement)

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“…Beyond the early interest in using nonimmunosuppressive cyclophilin inhibitors to target the human immunodeficiency virus (HIV), cyclosporine derivatives have played a prominent role in the race for pan-genotypic hepatitis C virus (HCV) antivirals. Involvement of cyclophilins in the life cycle of hepatitis C was first identified based on the efficacy of CsA against HCV in infected hepatocytes, and in HCV replicon assays .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A

Steadman¹,

Pettit²,

Poullennec³

et al. 2017

J. Med. Chem.

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Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.

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Section: Introductionmentioning

confidence: 99%