title: Highly resistant HIV-1 proteases and strategies for their inhibition.
abstract: The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease-catalyzed processing of the Gag-Pol precursor.
authors.affiliation: Department of Biology, Georgia State University, PO Box 4010, Atlanta, GA 30302-4010, USA.
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.affiliation: Department of Biology, Georgia State University, PO Box 4010, Atlanta, GA 30302-4010, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kneller
authors.affiliation: Department of Biology, Georgia State University, PO Box 4010, Atlanta, GA 30302-4010, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Wong-Sam
mesh_terms: D055162:Biocatalysis; D024882:Drug Resistance, Viral / Q000187:drug effects; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1