Molecules targeting a novel homotrimer cavity of Spike protein attenuate replication of SARS-CoV-2

Alison Daniels, Monikaben Padariya, Sarah Fletcher, Kathryn Ball, Ashita Singh, Neil Carragher, Ted Hupp, Christine Tait-Burkard, Umesh Kalathiya

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors that block viral entry. We have previously identified a novel proteinaceous cavity within the Spike protein homotrimer that could serve as a binding site for small molecules. However, it is not known whether these molecules would inhibit, stimulate, or have no effect on viral replication. To address this, we employed structural-based screening to identify small molecules that dock into the trimer cavity and assessed their impact on viral replication. Our findings show that a cohort of identified small molecules binding to the Spike trimer cavity effectively reduces the replication of various SARS-CoV-2 variants. These molecules exhibited inhibitory effects on B.1 (European original, D614G, EDB2) and B.1.617.2 (δ) variants, while showing moderate activity against the B.1.1.7 (α) variant. We further categorized these molecules into distinct groups based on their structural similarities. Our experiments demonstrated a dose-dependent viral replication inhibitory activity of these compounds, with some, like BCC0040453 exhibiting no adverse effects on cell viability even at high concentrations. Further investigation revealed that pre-incubating virions with compounds like BCC0031216 at different temperatures significantly inhibited viral replication, suggesting their specificity towards the S protein. Overall, our study highlights the inhibitory impact of a diverse set of chemical molecules on the biological activity of the Spike protein. These findings provide valuable insights into the role of the trimer cavity in the viral replication cycle and aid drug discovery programs aimed at targeting the coronavirus family.

Original languageEnglish
Article number105949
Pages (from-to)1-14
Number of pages14
JournalAntiviral Research
Volume228
Early online date26 Jun 2024
DOIs
Publication statusPublished - Aug 2024

Keywords / Materials (for Non-textual outputs)

  • SARS-CoV-2
  • Spike glycoprotein
  • infection
  • ACE2
  • homotrimer cavity
  • coronavirus
  • ligand screening

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