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

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

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.

Figures