期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 140, 期 43, 页码 14015-14018出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b07366
关键词
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资金
- NIH [T32 GM008349, T32 GM008600, R01 GM044783, P41 GM103399]
- Genentech predoctoral fellowship
- American Heart Association [09PRE2260125]
- Arnold O. Beckman Postdoctoral Fellowship
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- NSF [MCB 1518160]
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 BOHO center dot center dot center dot C hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short (r(O center dot center dot center dot O) = 2.2 angstrom), 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.
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