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Pharmacophore variants of the macrocyclic peptide triazole inactivator of HIV-1 Env

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Abstract

Previously we established a family of macrocyclic peptide triazoles (cPTs) that inactivate the Env protein complex of HIV-1, and identified the pharmacophore that engages Env’s receptor binding pocket. Here, we examined the hypothesis that the side chains of both components of the triazole Pro - Trp segment of cPT pharmacophore work in tandem to make intimate contacts with two proximal subsites of the overall CD4 binding site of gp120 to stabilize binding and function. Variations of the triazole Pro R group, which previously had been significantly optimized, led to identification of a derivative, MG-II-20, containing a pyrazole substitution. MG-II-20 has improved functional properties over previously examined cPTs, with KD for gp120 in the nM range. In contrast, new modifications of the Trp indole side chain, with either methyl- or bromo- components appended, had disruptive effects on gp120 binding, reflecting the sensitivity of function to changes in this component of the encounter complex. Plausible in silico models of cPT:gp120 complex structures were obtained that are consistent with the overall hypothesis of occupancy by the triazole Pro and Trp side chains, respectively, into the β20/21 and Phe43 sub-cavities. The overall results strengthen the definition of the cPT-Env inactivator binding site and provide a new lead composition (MG-II-20) as well as structure-function findings to guide future HIV-1 Env inactivator design.

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Acknowledgements

Research reported in this publication was supported by NIH GM56550/AI150471, PA Department of Health CURE grant SAP#4100083087 (2019 Formula Grant Program: Characterization of the Conformational Change Properties of the HIV-1 Envelope Protein), and an Undergraduate Research and Enrichment Program Minigrant to Monisha Gupta. S200 biosensor used in this work was supported by the Office of the Director, National Institutes of Health through NIH Award S10OD027009. We also acknowledge with gratitude the assistance of Dr. Chris Fritschi for discussions on synthetic strategy; Dr. Adel Ahmed Rashad and Aicha Bendia for compound design consultations and preliminary synthesis trial information; and Prof. Wayne Hendrickson for consultation on development of X-ray crystallographic tool compounds.

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Author notes

  1. These authors contributed equally: Monisha Gupta, Gabriela Canziani, Charles Ang, Mohammadjavad Mohammadi

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Medicine, Drexel University, Philadelphia, PA, 19102, USA

    Monisha Gupta, Gabriela Canziani, Charles Ang & Irwin Chaiken

  2. Department of Chemistry, College of Arts and Sciences, Drexel University, Philadelphia, PA, 19102, USA

    Monisha Gupta

  3. Department of Chemical & Biological Engineering, College of Engineering, Drexel University, Philadelphia, PA, 19102, USA

    Mohammadjavad Mohammadi & Cameron F. Abrams

  4. Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Derek Yang & Amos B. Smith III

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  1. Monisha Gupta
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Correspondence to Charles Ang or Irwin Chaiken.

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Gupta, M., Canziani, G., Ang, C. et al. Pharmacophore variants of the macrocyclic peptide triazole inactivator of HIV-1 Env. Med Chem Res 32, 1497–1509 (2023). https://doi.org/10.1007/s00044-023-03092-0

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