title: Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis.
abstract: There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the substrates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this region will tend to resist clinically relevant mutations. The present study offers the first prospective evaluation of this hypothesis, via computational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant proteases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envelope hypothesis as a guide to the design of robust protease inhibitors.
authors.affiliation: Center for Advanced Research in Biotechnology, University of Maryland, Biotechnology Institute, Rockville, MD 20850, USA.
authors.forename: Sripriya
authors.initials: S
authors.lastname: Chellappan
authors.forename: G S
authors.initials: GS
authors.lastname: Kiran Kumar Reddy
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: Madhavi N L
authors.initials: MN
authors.lastname: Nalam
authors.forename: Saima Ghafoor
authors.initials: SG
authors.lastname: Anjum
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Visvaldas
authors.initials: V
authors.lastname: Kairys
authors.forename: Miguel X
authors.initials: MX
authors.lastname: Fernandes
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
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
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D003461:Crystallography; D015195:Drug Design; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease