19F NMR-based fragment screening for 14 different biologically active RNAs and 10 DNA and protein counter-screens

  • We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
Author:Oliver BinasORCiDGND, Vanessa de JesusGND, Tom LandgrafORCiD, Albrecht Eduard VölkleinORCiD, Jason Martins, Daniel Hymon, Jasleen Kaur BainsORCiD, Hannes Berg, Thomas Biedenbänder, Boris FürtigORCiDGND, Santosh Lakshmi Gande, Anna Niesteruk, Andreas Oxenfarth, Nusrat QureshiORCiDGND, Tatjana SchamberORCiD, Robbin Schnieders, Alix Friederike TrösterGND, Anna WackerORCiDGND, Julia Wirmer-BartoschekORCiD, Maria Alexandra Wirtz MartinORCiD, Elke Stirnal, Kamal Azzaoui, Christian RichterORCiDGND, Sridhar Sreeramulu, Marcel Jules José Blommers, Harald SchwalbeORCiDGND
Parent Title (English):ChemBioChem
Place of publication:Weinheim
Document Type:Article
Date of Publication (online):2020/08/14
Date of first Publication:2020/08/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/03/09
Tag:19F; DNA-PAINT; FBS; RNA; fluorine; fragment-based screening; proteins
Page Number:11
First Page:423
Last Page:433
The work was supported by funds from DFG in collaborative research center 902: “Molecular principles of RNA-based regulation”, by EU-funded project iNEXT-discovery. Work at BMRZ is supported by the state of Hesse. V.D.J. was supported by Boehringer Ingelheim Fonds. R.S. was supported by Fonds der Chemischen Industrie. Open access funding enabled and organized by Projekt DEAL.
Institutes:Biochemie, Chemie und Pharmazie
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0