Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance
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 substrat...
| Main Authors: | , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101077 https://orcid.org/0000-0002-3320-3969 |
| _version_ | 1811079009907245056 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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. |
| author_sort | Nalam, Madhavi N. L. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:08:44Z |
| format | Article |
| id | mit-1721.1/101077 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:08:44Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1010772022-09-27T17:27:05Z Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance 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. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Altman, Michael D. Tidor, Bruce 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. National Institute of General Medical Sciences (U.S.) (Grant P01-GM66524) National Institute of General Medical Sciences (U.S.) (Grant AI41404) National Institute of General Medical Sciences (U.S.) (Grant AI43198) National Institute of General Medical Sciences (U.S.) (Grant GM065418) National Institute of General Medical Sciences (U.S.) (Grant GM082209) United States. American Recovery and Reinvestment Act of 2009 (Supplement P01GM066524-08S1) 2016-02-03T15:23:56Z 2016-02-03T15:23:56Z 2013-09 2013-07 Article http://purl.org/eprint/type/JournalArticle 10745521 http://hdl.handle.net/1721.1/101077 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. https://orcid.org/0000-0002-3320-3969 en_US http://dx.doi.org/10.1016/j.chembiol.2013.07.014 Chemistry & Biology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | 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. Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title | Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title_full | Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title_fullStr | Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title_full_unstemmed | Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title_short | Substrate Envelope-Designed Potent HIV-1 Protease Inhibitors to Avoid Drug Resistance |
| title_sort | substrate envelope designed potent hiv 1 protease inhibitors to avoid drug resistance |
| url | http://hdl.handle.net/1721.1/101077 https://orcid.org/0000-0002-3320-3969 |
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