Version 1
: Received: 2 March 2024 / Approved: 3 March 2024 / Online: 4 March 2024 (09:35:27 CET)
How to cite:
Freidel, M.R.; Armen, R.S. Research Progress on Spike-Dependent SARS CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike. Preprints2024, 2024030081. https://doi.org/10.20944/preprints202403.0081.v1
Freidel, M.R.; Armen, R.S. Research Progress on Spike-Dependent SARS CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike. Preprints 2024, 2024030081. https://doi.org/10.20944/preprints202403.0081.v1
Freidel, M.R.; Armen, R.S. Research Progress on Spike-Dependent SARS CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike. Preprints2024, 2024030081. https://doi.org/10.20944/preprints202403.0081.v1
APA Style
Freidel, M.R., & Armen, R.S. (2024). Research Progress on Spike-Dependent SARS CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike. Preprints. https://doi.org/10.20944/preprints202403.0081.v1
Chicago/Turabian Style
Freidel, M.R. and Roger S. Armen. 2024 "Research Progress on Spike-Dependent SARS CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike" Preprints. https://doi.org/10.20944/preprints202403.0081.v1
Abstract
Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts sought to identify small molecule antivirals with various mechanisms of action. Here we aim to review research progress on small molecule viral entry and fusion inhibitors that directly bind to the SARS CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in vitro SARS CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small molecule binding sites on Spike, it was unclear what the specific mechanism of action was, or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor binding domain (RBD) or N-terminal domain (NTD) and disrupt S1 receptor binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most mutations to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved with only a few observed mutations in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over numerous recent VOC mutant strains and/or greater broad spectrum antiviral activity for other more distantly related coronaviruses.
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
