Library versus library recognition and inhibition of the HIV-1 Nef allelome.
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.
Olszewski
Allison
A
Department of Chemistry, University of California, Irvine, California 92697-2025, USA.
Weiss
Gregory A
GA
D001665:Binding Sites; D015693:Gene Products, nef / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D019151:Peptide Library; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D019151:Peptide Library; D016159:Tumor Suppressor Protein p53; D054311:nef Gene Products, Human Immunodeficiency Virus