Discovery of Small Molecule Entry Inhibitors Targeting the Fusion Peptide of SARS-CoV-2 Spike Protein

  • ACS Med Chem Lett. 2021 Jul 28;12(8):1267-1274. doi: 10.1021/acsmedchemlett.1c00263.
Xin Hu  1 ,  Catherine Z Chen  1 ,  Miao Xu  1 ,  Zongyi Hu  2 ,  Hui Guo  1 ,  Zina Itkin  1 ,  Paul Shinn  1 ,  Parker Ivin  2 ,  Madeleine Leek  2 ,  T Jake Liang  2 ,  Min Shen  1 ,  Wei Zheng  1 ,  Matthew D Hall  1
Affiliations
  • 1. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States.
PMID: 34394844 DOI: 10.1021/acsmedchemlett.1c00263
Abstract

SARS-CoV-2 entry into host cells relies on the spike (S) protein binding to the human ACE2 receptor. In this study, we investigated the structural dynamics of the viral S protein at the fusion peptide (FP) domain and small molecule binding for therapeutics development. Following comparative modeling analysis and docking studies of our previously identified fusion inhibitor chlorcyclizine, we performed a pharmacophore-based virtual screen and identified two novel chemotypes of entry inhibitors targeting the FP. The compounds were evaluated in the pseudoparticle viral entry assay and SARS-CoV-2 cytopathic effect assay and showed single-digital micromole inhibition against SARS-CoV-2 as well as SARS-CoV-1 and MERS. The characterization of the FP binding site of SARS-CoV-2 S Protein provides a promising target for the structure-based development of small molecule entry inhibitors as drug candidates for the treatment of COVID-19.