Year: 2026
Type: article
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.
Source: NAR Molecular Medicine
Institutions: Immunology Frontier Research Center, The University of Osaka, Research Institute for Microbial Diseases, The University of Osaka, The University of Osaka, Institute for Protein Research, The University of Osaka, Kunsan National University, Center for Advanced Modalities and DDS, Osaka University
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,300
OpenAlex ID: W7215074242