Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid
Name
nihms-996282.pdf
Description
Accepted version
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661.71 KB
Format
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Checksum (MD5)
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Author(s)
Windsor, Ian William
Palte, Michael J.
Lukesh, John C.
Gold, Brian
Forest, Katrina T.
Raines, Ronald T
Date Issued
October 2018
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Windsor, Ian W. et al. "Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid." Journal of the American Chemical Society 140, 43 (October 2018): 14015-14018 © 2018 American Chemical Society
Version
Author's final manuscript
Abstract
Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallography demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short (rO···O = 2.2 Å), and density functional theory analysis reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-molecule ligands. Keywords: peptides and proteins; crystal structure; inhibitors; noncovalent interactions; functional groups
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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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.
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DOI of Published Version
https://doi.org/10.1021/jacs.8b07366
