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High Throughput Screening for Cyanovirin-N Mimetics Binding to HIV-1 gp4l

Intramural Research Support Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD and Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

James B. McMahon

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Tanya R. Johnson

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Barry R. O'Keefe

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Randy A. Buzzell

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Danielle Robbins

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Roberta Gardella

Intramural Research Support Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD and Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Jennifer Wilson

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

Michael R. Boyd

Molecular Targets Drug Discovery Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD

The human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp4l is an important mediator of viral entry into host cells. Previous studies showed that the virucidal protein cyanovirin-N (CV-N) bound to both gpl20 and gp4l, and that this binding was associated with its antiviral activity. We constructed an HTS assay based on the interaction of europium-labeled CV-N with recombinant glycosylated gp4l ectodomain to support identification of small-molecule mimetics of CV-N that might be developed as antiviral drug leads. Primary screening of over 107,000 natural product extracts in the assay yielded 347 confirmed hits. Secondary assays eliminated extracts that bound directly to labeled CV-N or for which the simple sugars mannose and N-acetylglucosamine blocked the interaction with gp4l (lectin activity). Extracts were further prioritized based on anti-HIV activity and other biological, biochemical, and chemical criteria. The distribution of source organism taxonomy of active extracts was analyzed, as was the cross-correlation of activity between the CV-N-gp4l binding competition assay and the previously reported CV-N-gpl20 binding competition assay. A limited set of extracts was selected for bioassay-guided fractionation.

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