Library versus library recognition and inhibition of the HIV-1 Nef allelome.

نویسندگان

  • Allison Olszewski
  • Gregory A Weiss
چکیده

Rapid evolution of drug-resistant viruses renders essentially all small-molecule antiviral treatments ineffective. We demonstrate an in vitro library versus library approach to identify small molecules targeting a broad spectrum of HIV-1 Nef protein variants. The technique could provide more effective antiviral therapies. First, a library of clinically derived Nef allelic variants, termed an allelome, was selected for function by binding to Nef ligands p53, actin, or p56lck. Next, a library of small-molecule inhibitors challenged the Nef allelome in competition assays. In contrast to single-variant inhibition, structurally simpler molecules could better inhibit the Nef allelome. Additionally, Nef sequences selected for binding to p53 resembled sequences from patients with a rapid progression to AIDS phenotype. Thus, the allelome versus small-molecule library approach offers a route for improving antiviral drug discovery and elucidating fundamental mechanisms of viral pathogenesis and resistance.

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عنوان ژورنال:
  • Journal of the American Chemical Society

دوره 127 35  شماره 

صفحات  -

تاریخ انتشار 2005