Discovery of Small Molecule Entry Inhibitors Targeting the Fusion Peptide of SARS-CoV-2 Spike Protein.
Xin HuCatherine Z ChenMiao XuZongyi HuHui GuoZina ItkinPaul ShinnParker IvinMadeleine LeekT Jake LiangMin ShenWei ZhengMatthew D HallPublished in: ACS medicinal chemistry letters (2021)
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.
Keyphrases
- sars cov
- small molecule
- protein protein
- respiratory syndrome coronavirus
- high throughput
- binding protein
- amino acid
- endothelial cells
- molecular dynamics
- cancer therapy
- induced apoptosis
- coronavirus disease
- drug delivery
- angiotensin ii
- electronic health record
- combination therapy
- induced pluripotent stem cells
- adverse drug
- dna binding
- high speed