Identification of small-molecule inhibitors of the immune system repressor Regnase-1.
9 affiliations
- 1Department of Genome Informatics, Research Institute for Microbial Diseases (RIMD), The University of Osaka, 565-0871Osaka, Japan.
- 2Laboratory for Systems Immunology, Immunology Frontier Research Center (WPI-iFReC), The University of Osaka, 565-0871Osaka, Japan.
- 3Laboratory of Host Defense, WPI-iFReC, The University of Osaka, 565-0871Osaka, Japan.
- 4TechnoPro, Inc. TechnoPro R&D, Company, 650-0047Kobe, Japan.
- 5Protein Crystallography Laboratory, Institute for Protein Research, The University of Osaka, 565-0871Osaka, Japan.
- 6Graduate School of Pharmaceutical Sciences, The University of Osaka, 565-0871Osaka, Japan.
- 7Department of Chemistry, Kunsan National University, 54150Gunsan, Republic of Korea.
- 8Department of Host Defense, RIMD, The University of Osaka, 565-0871Osaka, Japan.
- 9Center for Advanced Modalities and Drug Delivery System (CAMaD), The University of Osaka, 565-0871Osaka, Japan.
Abstract
Regnase-1 is an essential RNase that suppresses immune cell activation by targeting the mRNA of pro-inflammatory cytokines such as interleukin 6 (IL-6). Although genetic inhibition of Regnase-1 activity in CD8+ T cells has been shown to enhance antitumor immunity, no molecular inhibitors of Regnase-1 have been reported. By exploiting a library of nucleic acid analogs in conjunction with an RNA displacement assay, we identified multiple candidate competitors of Regnase-1 RNA substrates. Among these, suramin-an approved drug for treating African sleeping sickness-and several of its derivatives displaced Regnase-1 RNA targets with submicromolar affinity, competitively inhibited Regnase-1-mediated degradation of RNA in vitro, and enhanced Il6 mRNA levels and IL-6 production in mouse embryonic fibroblasts. A 2.62 Å crystal structure revealed that suramin bound to the Regnase-1 active site, coordinating with the catalytic Mg²⁺. Quantum chemical calculations further elucidated qualitative interactions between suramin and surrounding residues of Regnase-1. These findings establish suramin as a small-molecule inhibitor of Regnase-1-mediated RNA decay.
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BibTeX
@article{millius2026identification,
title = {{Identification of small-molecule inhibitors of the immune system repressor Regnase-1.}},
author = {Arthur Millius and Chee-Hong Takahiro Yew and Yuko Misumi and Jian Yu and Daisuke Takaya and Shuhei Miyakawa and Eun-Sol Choi and Hyo-Jun Lee and Tatum Melati Andini and Fahad Khalaf and Kazuhiko Maeda and Kaori Fukuzawa and Genji Kurisu and Shizuo Akira and Soyoung Park and Daron M Standley},
journal = {NAR molecular medicine},
year = {2026},
month = oct,
doi = {10.1093/narmme/ugag043},
url = {https://europepmc.org/article/MED/42909357},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of small-molecule inhibitors of the immune system repressor Regnase-1.
AU - Arthur Millius
AU - Chee-Hong Takahiro Yew
AU - Yuko Misumi
AU - Jian Yu
AU - Daisuke Takaya
AU - Shuhei Miyakawa
AU - Eun-Sol Choi
AU - Hyo-Jun Lee
AU - Tatum Melati Andini
AU - Fahad Khalaf
AU - Kazuhiko Maeda
AU - Kaori Fukuzawa
AU - Genji Kurisu
AU - Shizuo Akira
AU - Soyoung Park
AU - Daron M Standley
PY - 2026
DA - 2026/10/01
JO - NAR molecular medicine
DO - 10.1093/narmme/ugag043
UR - https://europepmc.org/article/MED/42909357
AB - Regnase-1 is an essential RNase that suppresses immune cell activation by targeting the mRNA of pro-inflammatory cytokines such as interleukin 6 (IL-6). Although genetic inhibition of Regnase-1 activity in CD8+ T cells has been shown to enhance antitumor immunity, no molecular inhibitors of Regnase-1 have been reported. By exploiting a library of nucleic acid analogs in conjunction with an RNA displacement assay, we identified multiple candidate competitors of Regnase-1 RNA substrates. Among these, suramin-an approved drug for treating African sleeping sickness-and several of its derivatives displaced Regnase-1 RNA targets with submicromolar affinity, competitively inhibited Regnase-1-mediated degradation of RNA in vitro, and enhanced Il6 mRNA levels and IL-6 production in mouse embryonic fibroblasts. A 2.62 Å crystal structure revealed that suramin bound to the Regnase-1 active site, coordinating with the catalytic Mg²⁺. Quantum chemical calculations further elucidated qualitative interactions between suramin and surrounding residues of Regnase-1. These findings establish suramin as a small-molecule inhibitor of Regnase-1-mediated RNA decay.
SN - 2976-856X
ER -