Discovery of direct-acting small-molecule RIG-I agonists through creation of a selective CARD activation platform
Abstract
Retinoic acid-inducible gene-I (RIG-I) plays a pivotal role in recognizing and combating RNA viruses in humans, and it has become a drug target of significant interest. RIG-I agonists composed of dsRNA represent antiviral and antitumor therapies, however the development of small-molecule RIG-I agonists, with their potential for improved pharmacokinetics, remains an unmet need. Here, we report small-molecule RIG-I agonists that directly activate the RIG-I receptor protein. These agonists stimulate the first step in RIG-I signaling by triggering release of the signaling domains (CARDs) from an autorepressed form of the protein. This was achieved by developing a sensitive high-throughput screening (HTS) assay that directly monitors CARD expulsion through optical methods. The resulting screen hits were refined and optimized, leading to a specific RIG-I agonist that induces a robust interferon response. This study establishes a pharmacophore and assay for development of small molecules that precisely modulate RIG-I signaling.
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BibTeX
@article{guo2026discovery,
title = {{Discovery of direct-acting small-molecule RIG-I agonists through creation of a selective CARD activation platform}},
author = {Rong Guo and Kenneisha Norford and Ling Xu and Manyi Wei and Wenshuai Wang and Stephanie Halene and Anna Marie Pyle},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77982-3},
url = {https://www.nature.com/articles/s41467-026-77982-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Discovery of direct-acting small-molecule RIG-I agonists through creation of a selective CARD activation platform
AU - Rong Guo
AU - Kenneisha Norford
AU - Ling Xu
AU - Manyi Wei
AU - Wenshuai Wang
AU - Stephanie Halene
AU - Anna Marie Pyle
PY - 2026
DA - 2026/10/19
JO - Nature Communications
DO - 10.1038/s41467-026-77982-3
UR - https://www.nature.com/articles/s41467-026-77982-3
AB - Retinoic acid-inducible gene-I (RIG-I) plays a pivotal role in recognizing and combating RNA viruses in humans, and it has become a drug target of significant interest. RIG-I agonists composed of dsRNA represent antiviral and antitumor therapies, however the development of small-molecule RIG-I agonists, with their potential for improved pharmacokinetics, remains an unmet need. Here, we report small-molecule RIG-I agonists that directly activate the RIG-I receptor protein. These agonists stimulate the first step in RIG-I signaling by triggering release of the signaling domains (CARDs) from an autorepressed form of the protein. This was achieved by developing a sensitive high-throughput screening (HTS) assay that directly monitors CARD expulsion through optical methods. The resulting screen hits were refined and optimized, leading to a specific RIG-I agonist that induces a robust interferon response. This study establishes a pharmacophore and assay for development of small molecules that precisely modulate RIG-I signaling.
SN - 2041-1723
ER -