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Inhibition of a viral enzyme by a small-molecule dimer disruptor.

ABSTRACT: We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-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.

SUBMITTER: Shahian T

PROVIDER: S-EPMC2752665 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Inhibition of a viral enzyme by a small-molecule dimer disruptor.

Shahian Tina T Lee Gregory M GM Lazic Ana A Arnold Leggy A LA Velusamy Priya P Roels Christina M CM Guy R Kiplin RK Craik Charles S CS

Nature chemical biology 20090726 9

We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-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 inhibi ...[more]

PMID: 19633659

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