title: 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Nese
authors.initials: N
authors.lastname: Kurt Yilmaz
authors.affiliation: Department of Biochemistry and Biophysics, and the UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Swanstrom
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. Electronic address: Celia.Schiffer@umassmed.edu.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D011480:Protease Inhibitors / Q000627:therapeutic use*
chemical_list: D011480:Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: HIV-1 protease; drug resistance; protease inhibitors; resistance mutations; structure-based drug design; substrate envelope