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

Nat Chem Biol. 2009 Sep;5(9):640-6. doi: 10.1038/nchembio.192. Epub 2009 Jul 26.

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.

MeSH terms

  • Binding Sites
  • Herpesvirus 8, Human / drug effects*
  • Herpesvirus 8, Human / enzymology*
  • Herpesvirus 8, Human / genetics
  • Humans
  • Models, Molecular
  • Point Mutation
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • Protein Multimerization / drug effects*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Substrate Specificity

Substances

  • Protease Inhibitors
  • Small Molecule Libraries

Associated data

  • PubChem-Substance/81055042
  • PubChem-Substance/81055043
  • PubChem-Substance/81067414
  • PubChem-Substance/81067415
  • PubChem-Substance/81067416
  • PubChem-Substance/81067417
  • PubChem-Substance/81067418
  • PubChem-Substance/81067419
  • PubChem-Substance/81067420
  • PubChem-Substance/81067421
  • PubChem-Substance/81067422
  • PubChem-Substance/81067423
  • PubChem-Substance/81067424
  • PubChem-Substance/81067425
  • PubChem-Substance/81067426
  • PubChem-Substance/81067427
  • PubChem-Substance/81067428
  • PubChem-Substance/81067429
  • PubChem-Substance/81067430
  • PubChem-Substance/81067431
  • PubChem-Substance/81067432
  • PubChem-Substance/81067433
  • PubChem-Substance/81067434
  • PubChem-Substance/81067435
  • PubChem-Substance/81067436
  • PubChem-Substance/81067437