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

Xin Hu; Catherine Z Chen; Miao Xu; Zongyi Hu; Hui Guo; Zina Itkin; Paul Shinn; Parker Ivin; Madeleine Leek; T Jake Liang; Min Shen; Wei Zheng; Matthew D Hall

doi:10.1021/acsmedchemlett.1c00263

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. eCollection 2021 Aug 12.

Authors

Xin Hu¹, Catherine Z Chen¹, Miao Xu¹, Zongyi Hu², Hui Guo¹, Zina Itkin¹, Paul Shinn¹, Parker Ivin², Madeleine Leek², T Jake Liang², Min Shen¹, Wei Zheng¹, Matthew D Hall¹

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.

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.