Structure-activity relationship of flavin analogs that target the FMN riboswitch
Structure-activity relationship of flavin analogs that target the FMN riboswitch
ABSTRACT The flavin mononucleotide (FMN) riboswitch is an emerging target for the development of novel RNA-targeting antibiotics. We previously discovered an FMN derivative —5FDQD— that protects mice against diarrhea-causing Clostridium difficile bacteria. Here, we present the structure-based drug design strategy that led to the discovery of this fluoro-phenyl derivative with antibacterial properties. This approach involved the following stages: (1) structural analysis of all available free and bound FMN riboswitch structures; (2) design, synthesis and purification of derivatives; (3) in vitro testing for productive binding using two chemical probing methods; (4) in vitro transcription termination assays; (5) resolution of the crystal structures of the FMN riboswitch in complex with the most mature candidates. In the process, we delineated principles for productive binding to this riboswitch, thereby demonstrating the effectiveness of a coordinated structure-guided approach to designing drugs against RNA. GRAPHICAL ABSTRACTbiorxiv;389148v1/UFIG1F1ufig1Exploring the chemical structure landscape of FMN riboswitch binders.
Vicens Quentin、Reyes Francis E.、Berman Paul Aristoff Judd、Kaur Harpreet、Gadwood Robert C.、Schostarez Heinrich J.、Blount Kenneth F.、Suto Robert K.、Wickens Phil、Mondrag¨?n Estefan¨aa、Kells Kevin W.、Batey Robert T.、Coish Philip、Wilson Jeffery
Department of Chemistry and Biochemistry, University of ColoradoDepartment of Chemistry and Biochemistry, University of ColoradoDalton Pharma ServicesDalton Pharma ServicesKalexsynKalexsynBioRelixXtal BioStructuresDalton Pharma ServicesDepartment of Chemistry and Biochemistry, University of ColoradoDalton Pharma ServicesDepartment of Chemistry and Biochemistry, University of ColoradoBioRelixDalton Pharma Services
药学生物科学研究方法、生物科学研究技术分子生物学
Vicens Quentin,Reyes Francis E.,Berman Paul Aristoff Judd,Kaur Harpreet,Gadwood Robert C.,Schostarez Heinrich J.,Blount Kenneth F.,Suto Robert K.,Wickens Phil,Mondrag¨?n Estefan¨aa,Kells Kevin W.,Batey Robert T.,Coish Philip,Wilson Jeffery.Structure-activity relationship of flavin analogs that target the FMN riboswitch[EB/OL].(2025-03-28)[2025-08-18].https://www.biorxiv.org/content/10.1101/389148.点此复制
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