ABSTRACT
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.
Subject(s)
Antiviral Agents/pharmacology , Chemistry, Pharmaceutical/methods , Hepacivirus/enzymology , Quinolones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Site , Antiviral Agents/chemical synthesis , Binding Sites , Crystallography, X-Ray/methods , Drug Design , Hydrogen Bonding , Hydrolysis , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Quinolones/chemical synthesis , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry , X-RaysABSTRACT
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Quinolones/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Binding Sites , Computer Simulation , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Efforts towards developing orally bioavailable HIV-1 maturation inhibitors starting from betulinic acid 1 are described. SAR resulted in improved potency, physicochemical properties, and enhanced oral absorption in rats.
