A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation
Abstract
The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here, we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in the central cavity of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication and inflammation in the lungs of XBB.1.5-infected female mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.
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BibTeX
@article{mou2026sarscov2,
title = {{A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation}},
author = {Huihui Mou and Bo Gao and Gang Ye and Divyasha Saxena and Lizhou Zhang and Fan Bu and Jyoti Vishwakarma and Yulia Getmanenko and Shuo Zhou and Claudia Ruiz Bayona and Li Lin and Janarjan Bhandari and Charles C. Bailey and Gogce C. Crynen and Claire E. Kitzmiller and Hao Li and Yuka Otsuka and Lalit Batra and Stuart Weston and Matthew B. Frieman and David K. Meyerholz and Louis Scampavia and Timothy P. Spicer and Reuben S. Harris and Michael D. Cameron and Thomas D. Bannister and Jian Zheng and Michael Farzan and Fang Li and Hyeryun Choe},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78835-9},
url = {https://www.nature.com/articles/s41467-026-78835-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation
AU - Huihui Mou
AU - Bo Gao
AU - Gang Ye
AU - Divyasha Saxena
AU - Lizhou Zhang
AU - Fan Bu
AU - Jyoti Vishwakarma
AU - Yulia Getmanenko
AU - Shuo Zhou
AU - Claudia Ruiz Bayona
AU - Li Lin
AU - Janarjan Bhandari
AU - Charles C. Bailey
AU - Gogce C. Crynen
AU - Claire E. Kitzmiller
AU - Hao Li
AU - Yuka Otsuka
AU - Lalit Batra
AU - Stuart Weston
AU - Matthew B. Frieman
AU - David K. Meyerholz
AU - Louis Scampavia
AU - Timothy P. Spicer
AU - Reuben S. Harris
AU - Michael D. Cameron
AU - Thomas D. Bannister
AU - Jian Zheng
AU - Michael Farzan
AU - Fang Li
AU - Hyeryun Choe
PY - 2026
DA - 2026/10/27
JO - Nature Communications
DO - 10.1038/s41467-026-78835-9
UR - https://www.nature.com/articles/s41467-026-78835-9
AB - The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here, we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in the central cavity of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication and inflammation in the lungs of XBB.1.5-infected female mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.
SN - 2041-1723
ER -