Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds
Name
Shen-2013-Testing the Substrate.pdf
Size
5.14 MB
Format
Adobe PDF
Checksum (MD5)
5eb71770771d2a12171fae90be37e517
Author(s)
Shen, Yang
Altman, Michael D.
Ali, Akbar
Nalam, Madhavi N. L.
Cao, Hong
Rana, Tariq M.
Schiffer, Celia A.
Tidor, Bruce
Date Issued
November 2013
Journal
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
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
Terms of Use
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.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1021/cb400468c
