Host soluble inositol phosphate signaling promotes coronavirus replication
- 1National Institute of Environmental Health Sciences
Abstract
Coronaviruses rely extensively on host pathways for replication, making host-directed therapies an attractive strategy for broad-spectrum antivirals with reduced risk of viral resistance. Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.
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BibTeX
@misc{shats2026host,
title = {{Host soluble inositol phosphate signaling promotes coronavirus replication}},
author = {I. Shats and H. Wang and Y. Zhou and C. Gu and A. Carr and C. M. Guardia and S. Shears and R. E. Stanley and Q. Zhang and R. Blind and X. Wang and X. Li},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751050},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751050v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Host soluble inositol phosphate signaling promotes coronavirus replication
AU - I. Shats
AU - H. Wang
AU - Y. Zhou
AU - C. Gu
AU - A. Carr
AU - C. M. Guardia
AU - S. Shears
AU - R. E. Stanley
AU - Q. Zhang
AU - R. Blind
AU - X. Wang
AU - X. Li
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751050
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751050v1
AB - Coronaviruses rely extensively on host pathways for replication, making host-directed therapies an attractive strategy for broad-spectrum antivirals with reduced risk of viral resistance. Here we identify the host soluble inositol phosphate pathway as a previously unrecognized dependency for coronavirus infection. Genetic or pharmacologic inhibition of several kinases in this pathway markedly suppresses replication of both alpha- and betacoronaviruses, while increasing pathway activity promotes viral replication. We developed UNC7844, a potent multi-target inhibitor of these kinases, which reduces coronavirus replication by more than four orders of magnitude in cultured cells and suppresses coronavirus infection in mice. Mechanistically, UNC7844 suppresses inositol (pyro)phosphates production, disrupts phosphoinositide homeostasis, and impairs late endosomal dynamics, blocking early post-entry steps required for viral genome release and replication. Together, our findings establish the soluble inositol (pyro)phosphate pathway as an important regulator of coronavirus infection and highlight its inhibition as a promising host-directed antiviral strategy.
ER -