Inhibition of a viral enzyme by a small-molecule dimer disruptor. Nat Chem Biol 2009 Sep;5(9):640-6
Date
07/28/2009Pubmed ID
19633659Pubmed Central ID
PMC2752665DOI
10.1038/nchembio.192Scopus ID
2-s2.0-69249156893 (requires institutional sign-in at Scopus site) 73 CitationsAbstract
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.
Author List
Shahian T, Lee GM, Lazic A, Arnold LA, Velusamy P, Roels CM, Guy RK, Craik CSAuthor
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Binding SitesHerpesvirus 8, Human
Humans
Models, Molecular
Point Mutation
Protease Inhibitors
Protein Conformation
Protein Multimerization
Small Molecule Libraries
Substrate Specificity
