Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis

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 sub strates 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 pros pective evaluation of this hypothesis, via compu tational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant pro teases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envel ope hypothesis as a guide to the design of robust protease inhibitors.

Keywords

AIDS Crystal Drug design Inhibitor Protease . Faculdade de Ciências Exatas e da Engenharia

URI

http://hdl.handle.net/10400.13/5007

Citation

hellappan, S., Kiran Kumar Reddy, G. S., Ali, A., Nalam, M. N., Anjum, S. G., Cao, H., ... & Gilson, M. K. (2007). Design of mutation‐resistant HIV protease inhibitors with the substrate envelope hypothesis. Chemical Biology & Drug Design, 69(5), 298-313.