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- Title
Inhibition of a viral enzyme by a small-molecule dimer disruptor.
- Authors
Shahian, Tina; Lee, Gregory M.; Lazic, Ana; Arnold, Leggy A.; Velusamy, Priya; Roels, Christina M.; Guy, R. Kiplin; Craik, Charles S.
- Abstract
We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma–associated herpesvirus (KSHV) by screening an α-helical mimetic library. Next, we synthesized a second generation of low-micromolar inhibitors with improved potency and solubility. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N HSQC titration studies mapped the inhibitor binding site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small-molecule inhibitors.
- Subjects
KAPOSI'S sarcoma; DIMERS; OLIGOMERS; POLYMERS; MACROMOLECULES; ENZYME inhibitors; SARCOMA
- Publication
Nature Chemical Biology, 2009, Vol 5, Issue 9, p640
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.192