title: Enhancing protein backbone binding--a fruitful concept for combating drug-resistant HIV.
abstract: The evolution of drug resistance is one of the most fundamental problems in medicine. In HIV/AIDS, the rapid emergence of drug-resistant HIV-1 variants is a major obstacle to current treatments. HIV-1 protease inhibitors are essential components of present antiretroviral therapies. However, with these protease inhibitors, resistance occurs through viral mutations that alter inhibitor binding, resulting in a loss of efficacy. This loss of potency has raised serious questions with regard to effective long-term antiretroviral therapy for HIV/AIDS. In this context, our research has focused on designing inhibitors that form extensive hydrogen-bonding interactions with the enzyme's backbone in the active site. In doing so, we limit the protease's ability to acquire drug resistance as the geometry of the catalytic site must be conserved to maintain functionality. In this Review, we examine the underlying principles of enzyme structure that support our backbone-binding concept as an effective means to combat drug resistance and highlight their application in our recent work on antiviral HIV-1 protease inhibitors.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: David D
authors.initials: DD
authors.lastname: Anderson
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding
chemical_list: D017320:HIV Protease Inhibitors