title: Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance.
abstract: The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against different clades of HIV as well as a panel of 12 drug-resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Madhavi N L
authors.initials: MN
authors.lastname: Nalam
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: G S Kiran Kumar
authors.initials: GS
authors.lastname: Reddy
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Saima G
authors.initials: SG
authors.lastname: Anjum
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.forename: Nese Kurt
authors.initials: NK
authors.lastname: Yilmaz
authors.forename: Bruce
authors.initials: B
authors.lastname: Tidor
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D011485:Protein Binding; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1