Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance
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Tidor_Substrate envelope.pdf
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Author(s)
Nalam, Madhavi N. L.
Ali, Akbar
Reddy, G.S. Kiran Kumar
Cao, Hong
Anjum, Saima G.
Altman, Michael D.
Yilmaz, Nese Kurt
Tidor, Bruce
Rana, Tariq M.
Schiffer, Celia A.
Date Issued
September 2013
Journal
Chemistry & Biology
Publisher
Elsevier
Citation
Nalam, Madhavi N.L., Akbar Ali, G.S. Kiran Kumar Reddy, Hong Cao, Saima G. Anjum, Michael D. Altman, Nese Kurt Yilmaz, Bruce Tidor, Tariq M. Rana, and Celia A. Schiffer. “Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance.” Chemistry & Biology 20, no. 9 (September 2013): 1116–1124.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.chembiol.2013.07.014
