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Updated: Mar 29, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor
Francesca Curreli1, Kashfia Haque1, Lihua Xie2
1Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Abstract:
One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors.
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