Combating susceptibility to drug resistance: lessons from HIV-1 protease.
Drug resistance is a major obstacle in modern medicine. However, resistance is rarely considered in drug development and may inadvertently be facilitated, as many designed inhibitors contact residues that can mutate to confer resistance, without significantly impairing function. Contemporary drug design often ignores the detailed atomic basis for function and primarily focuses on disrupting the target's activity, which is necessary but not sufficient for developing a robust drug. In this study, we examine the impact of drug-resistant mutations in HIV-1 protease on substrate recognition and demonstrate that most primary active site mutations do not extensively contact substrates, but are critical to inhibitor binding. We propose a general, structure-based strategy to reduce the probability of drug resistance by designing inhibitors that interact only with those residues that are essential for function.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
Nancy M
NM
King
Moses
M
Prabu-Jeyabalan
Ellen A
EA
Nalivaika
Celia A
CA
Schiffer
D001665:Binding Sites / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D016333:HIV Protease / Q000138:chemical synthesis* / Q000235:genetics / Q000502:physiology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D017320:HIV Protease Inhibitors; D016333:HIV Protease