Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond

Abstract

Drug resistance is prevalent across many diseases, rendering therapies ineffective with severe financial and health consequences. Rather than accepting resistance after the fact, proactive strategies need to be incorporated into the drug design and development process to minimize the impact of drug resistance. These strategies can be derived from our experience with viral disease targets where multiple generations of drugs had to be developed to combat resistance and avoid antiviral failure. Significant efforts including experimental and computational structural biology, medicinal chemistry, and machine learning have focused on understanding the mechanisms and structural basis of resistance against direct-acting antiviral (DAA) drugs. Integrated methods show promise for being predictive of resistance and potency. In this review, we give an overview of this research for human immunodeficiency virus type 1, hepatitis C virus, and influenza virus and the lessons learned from resistance mechanisms of DAAs. These lessons translate into rational strategies to avoid resistance in drug design, which can be generalized and applied beyond viral targets. While resistance may not be completely avoidable, rational drug design can and should incorporate strategies at the outset of drug development to decrease the prevalence of drug resistance.

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

“…39 The genetic barrier to resistance for protease inhibitors is generally moderate to low, as shown by HIV and HCV protease inhibitors. 40 Resistance to Paxlovid is expected to rise with the increasing prescription. In addition, nirmatrelvir ( 3 ) is used in combination with ritonavir in clinics to prolong its half-life.…”

Viral proteases: Structure, mechanism and inhibition

“…Recent studies combining parallel molecular dynamics simulations and machine learning have provided insights into how remote changes can confer resistance and which interactions are most indicative of these changes [7] , [20] . Each of the FDA-approved HIV-1 protease inhibitors has specific signature mutations that cause resistance; detailed reviews can be found elsewhere [3] , [19] , [21] , [22] , [23] , [24] , [25] .…”

Computational anti-COVID-19 drug design: progress and challenges

“…Designing novel drugs for new diseases is a complicated process necessary to find molecules that bind to specific biomolecular targets and have good physical and chemical properties over a broad chemical space [ 147 ]. First, knowledge of the virus and target is necessary.…”