Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis
Authors
Chellappan, SripriyaReddy, G. S. Kiran Kumar
Ali, Akbar
Nalam, Madhavi N. L.
Anjum, Saima G.
Cao, Hong
Kairys, Visvaldas
Fernandes, Miguel X.
Altman, Michael D.
Tidor, Bruce
Rana, Tariq M.
Schiffer, Celia A.
Gilson, Michael K.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2007-06-02Keywords
CrystallographyDrug Design
HIV Protease
HIV Protease Inhibitors
Magnetic Resonance Spectroscopy
*Mutation
Spectrometry, Mass, Electrospray Ionization
Substrate Specificity
Biochemistry, Biophysics, and Structural Biology
Pharmacology, Toxicology and Environmental Health
Metadata
Show full item recordAbstract
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.Source
Chem Biol Drug Des. 2007 May;69(5):298-313. Link to article on publisher's siteDOI
10.1111/j.1747-0285.2007.00514.xPermanent Link to this Item
http://hdl.handle.net/20.500.14038/26134PubMed ID
17539822Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1111/j.1747-0285.2007.00514.x