Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds
Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors...
| Main Authors: | , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Chemical Society (ACS)
2015
|
| Online Access: | http://hdl.handle.net/1721.1/96804 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-1703-7796 |
| _version_ | 1811080833619984384 |
|---|---|
| author | Shen, Yang Altman, Michael D. Ali, Akbar Nalam, Madhavi N. L. Cao, Hong Rana, Tariq M. Schiffer, Celia A. Tidor, Bruce |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Shen, Yang Altman, Michael D. Ali, Akbar Nalam, Madhavi N. L. Cao, Hong Rana, Tariq M. Schiffer, Celia A. Tidor, Bruce |
| author_sort | Shen, Yang |
| collection | MIT |
| description | Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al. J. Am. Chem. Soc. 2008, 130, 6099–6113]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope, a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations. |
| first_indexed | 2024-09-23T11:37:17Z |
| format | Article |
| id | mit-1721.1/96804 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:37:17Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/968042022-09-27T20:47:47Z Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds Shen, Yang Altman, Michael D. Ali, Akbar Nalam, Madhavi N. L. Cao, Hong Rana, Tariq M. Schiffer, Celia A. Tidor, Bruce Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Shen, Yang Altman, Michael D. Tidor, Bruce Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al. J. Am. Chem. Soc. 2008, 130, 6099–6113]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope, a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations. National Science Foundation (U.S.) (NSF grant 0821391) National Institute of General Medical Sciences (U.S.) (NIH (GM066524)) National Institute of General Medical Sciences (U.S.) (GM065418) National Institute of General Medical Sciences (U.S.) (the NIH (GM082209) National Institute of General Medical Sciences (U.S.) (AI41404) National Institute of General Medical Sciences (U.S.) (AI43198) 2015-04-24T19:06:38Z 2015-04-24T19:06:38Z 2013-11 2013-06 Article http://purl.org/eprint/type/JournalArticle 1554-8929 1554-8937 http://hdl.handle.net/1721.1/96804 Shen, Yang, Michael D. Altman, Akbar Ali, Madhavi N. L. Nalam, Hong Cao, Tariq M. Rana, Celia A. Schiffer, and Bruce Tidor. “Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds.” ACS Chemical Biology 8, no. 11 (November 15, 2013): 2433–2441. © 2013 American Chemical Society. https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-1703-7796 en_US http://dx.doi.org/10.1021/cb400468c ACS Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) American Chemical Society |
| spellingShingle | Shen, Yang Altman, Michael D. Ali, Akbar Nalam, Madhavi N. L. Cao, Hong Rana, Tariq M. Schiffer, Celia A. Tidor, Bruce Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title | Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title_full | Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title_fullStr | Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title_full_unstemmed | Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title_short | Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds |
| title_sort | testing the substrate envelope hypothesis with designed pairs of compounds |
| url | http://hdl.handle.net/1721.1/96804 https://orcid.org/0000-0002-3320-3969 https://orcid.org/0000-0002-1703-7796 |
| work_keys_str_mv | AT shenyang testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT altmanmichaeld testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT aliakbar testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT nalammadhavinl testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT caohong testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT ranatariqm testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT schifferceliaa testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds AT tidorbruce testingthesubstrateenvelopehypothesiswithdesignedpairsofcompounds |