SARS-CoV-2 nsp13 helicase is an essential enzyme for viral replication and a promising target for antiviral drug development. This study compares the double-stranded RNA (dsRNA) unwinding activity of nsp13 and the Omicron nsp13 variant, which is predominant in currently circulating lineages. Using in vitro gel- and fluorescence-based assays, we found that both nsp13 and nsp13 have dsRNA unwinding activity with equivalent kinetics. Furthermore, the R392C mutation had no effect on the efficiency of the nsp13-specific helicase inhibitor SSYA10-001. We additionally confirmed the activity of several other helicase inhibitors against nsp13, including punicalagin that inhibited dsRNA unwinding at nanomolar concentrations. Overall, this study reveals the utility of using dsRNA unwinding assays to screen small molecules for antiviral activity against nsp13 and the Omicron nsp13 variant. Continual monitoring of newly emergent variants will be essential for considering resistance profiles of lead compounds as they are advanced towards next-generation therapeutic development.
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http://dx.doi.org/10.1016/j.slasd.2024.01.006 | DOI Listing |
Nucleic Acids Res
December 2024
Biomimetic Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 4a, Dortmund 44227, Germany.
Group II introns are ancient self-splicing ribozymes and retrotransposons. Though long speculated to have originated before translation, their dependence on intron-encoded proteins for splicing and mobility has cast doubt on this hypothesis. While some group II introns are known to retain part of their catalytic repertoire in the absence of protein cofactors, protein-free complete reverse splicing of a group II intron into a DNA target has never been demonstrated.
View Article and Find Full Text PDFAnal Chem
November 2024
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Mol Cell Biochem
October 2024
Center for Cardiovascular Genetic Studies, Institute of Molecular Medicine, The University of Texas Health Science Center, 6770 Bertner Street, Suite C900A, Houston, TX, 77030, USA.
Biophys J
November 2024
School of Biosciences, University of Birmingham, Birmingham, United Kingdom; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. Electronic address:
DEAD-box helicases use ATP to unwind short double-stranded RNA (dsRNA). The helicase core consists of two discrete domains, termed RecA_N and RecA_C. The nucleotide binding site is harbored in RecA_N, while both RecA_N and RecA_C are involved in RNA recognition and ATP hydrolysis.
View Article and Find Full Text PDFCell
September 2024
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research at MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA. Electronic address:
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