Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer.

Bioorg Med Chem Lett

Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address:

Published: July 2017

AI Article Synopsis

  • - The HIV protein HIVgp41 is a key target for drugs due to its role in viral entry, and past research has found inhibitors that prevent important structural formations needed for this process.
  • - This study identified and tested 113 compounds related to previously reported inhibitors that block a specific part of the HIVgp41 structure, focusing on two different fusion assays to evaluate effectiveness.
  • - Compound #11 was identified as the most promising candidate, showing strong activity with low toxicity, specificity for HIVgp41, and engagement with the target protein similar to natural components, as confirmed by simulations.

Article Abstract

The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett.2015, 25 2853-59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC=37.81µM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551449PMC
http://dx.doi.org/10.1016/j.bmcl.2017.05.020DOI Listing

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