Improving Viral Protease Inhibitors to Counter Drug Resistance

Abstract

Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design.

Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease

“…44,46 In addition to staying within the substrate envelope, inhibitors need to balance the rigidity required for stable target interactions and flexibility to adapt to changes due to resistance mutations and binding site dynamics. 38,49 The network hypothesis explains how changes in conformational dynamics due to mutations, located even away from the active site, can be propagated to the active site to affect inhibitor binding. 51 Thus, target protein and inhibitor dynamics are essential components of molecular mechanisms leading to the emergence of drug resistance in HCV NS3/4A protease.…”

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

“…39–41 Another approach applied to design PIs with improved resistant profiles involves incorporation of conformational flexibility that can allow the inhibitor to adapt to structural changes in the protease active site due to mutations. 35 Here, we describe a structure-guided strategy that combines these two approaches and, together with our understanding of the mechanisms of drug resistance, led to the design of NS3/4A PIs with exceptional potency profiles against major drug resistant HCV variants.…”

In vitro methods for testing antiviral drugs

“…Alternatively, cleavage products may be monitored by analysis of proteolytic products by mass spectrometric methods (Hu et al, 2015;Joshi et al, 2017;Lathia et al, 2011;Rumlová et al, 2003), analytical HPLC (Teruya et al, 2016), or electrochemical methods based on the difference in penetration of substrate and cleavage products through the membrane of a polyionselective sensor (Gemene and Meyerhoff, 2011;Han et al, 1996). To study the specificity of inhibitor binding and to extend the research to rational design of inhibitors, X-ray or NMR structures of proteases in complex with the inhibitor may be determined, as reported in numerous cases for the proteases of HIV-1 [reviewed in (Ghosh et al, 2016)], HCV (Yilmaz et al, 2016), and MERS .…”