Title
Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2007-06-02
Document Type
Article
Subjects
Crystallography; Drug Design; HIV Protease; HIV Protease Inhibitors; Magnetic Resonance Spectroscopy; *Mutation; Spectrometry, Mass, Electrospray Ionization; Substrate Specificity
Disciplines
Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health
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.
DOI of Published Version
10.1111/j.1747-0285.2007.00514.x
Source
Chem Biol Drug Des. 2007 May;69(5):298-313. Link to article on publisher's site
Journal/Book/Conference Title
Chemical biology and drug design
Related Resources
PubMed ID
17539822
Repository Citation
Chellappan S, Reddy G, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK. (2007). Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Biochemistry and Molecular Pharmacology Publications. https://doi.org/10.1111/j.1747-0285.2007.00514.x. Retrieved from https://escholarship.umassmed.edu/bmp_pp/72