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Spontaneous base flipping helps drive Nsp15's preferences in double stranded RNA substrates.
Nat Commun
January 2025
Molecular and Cellular Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 T. W. Alexander Drive, Research Triangle Park, NC, 27709, USA.
Coronaviruses evade detection by the host immune system with the help of the endoribonuclease Nsp15, which regulates levels of viral double stranded RNA by cleaving 3' of uridine (U). While prior structural data shows that to cleave double stranded RNA, Nsp15's target U must be flipped out of the helix, it is not yet understood whether Nsp15 initiates flipping or captures spontaneously flipped bases. We address this gap by designing fluorinated double stranded RNA substrates that allow us to directly relate a U's sequence context to both its tendency to spontaneously flip and its susceptibility to cleavage by Nsp15.
View Article and Find Full Text PDFF-FLT PET and Blood-based Biomarkers for Identifying Gastrointestinal Graft versus Host Disease after Allogeneic Cell Transplantation.
Radiol Imaging Cancer
January 2025
From the Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE 10th St, Oklahoma City, OK 73104 (J.H.C., L.M., S.K.V., Z.H., M.P., J.G., Y.W.); Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY (J.L., J.F.); Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma, Oklahoma City, Okla (S.K.V., T.G.); Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md (C.G.K., R.G.); Department of Biomedical Engineering, University of Central Oklahoma, Edmond, Okla (Z.H.); and Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA (K.M.W.).
Purpose To determine whether fluorine 18 (F) fluorothymidine (FLT) PET imaging alone or combined with Mount Sinai Acute GVHD International Consortium (MAGIC) biomarkers could help identify subclinical gastrointestinal graft versus host disease (GI-GVHD) by day 100 following hematopoietic stem cell transplantation (HSCT). Materials and Methods F-FLT PET imaging was analyzed in a prospective pilot study (ClinicalTrials.gov identifier no.
View Article and Find Full Text PDFA flexible and scalable synthesis of 4'-thionucleosides.
Chem Sci
December 2024
Department of Chemistry, Simon Fraser University Burnaby British Columbia V5A 1S6 Canada
4'-Thionucleosides (thNAs) are synthetic nucleoside analogues that have attracted attention as leads for drug discovery in oncology and virology. Here we report a thNA synthesis that relies on a scalable α-fluorination and aldol reaction of α-heteroaryl acetaldehydes followed by a streamlined process involving carbonyl reduction, mesylate formation and a double displacement reaction using NaSH. We demonstrate the multigram preparation of 4'-thio-5-methyluridine and highlight the production of purine and pyrimidine thNAs as well as C2'-modified thNAs.
View Article and Find Full Text PDFExploring Fluorinase Substrate Tolerance at C-2 of SAM.
Chembiochem
January 2025
School of Chemistry and Biomedical Sciences Research Centre, University of St Andrews, North Haugh, KY16 9ST, St Andrews, UK.
The fluorinase enzyme (EC 2.5.1.
View Article and Find Full Text PDF2'-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects.
Natl Sci Rev
October 2024
College of Chemistry, Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Zhengzhou University, Zhengzhou 450001, China.
Fluorinated nucleosides are an important class of modified nucleosides that have demonstrated therapeutic potential for treating various human diseases, especially viral infections and cancer. Many fluorinated nucleosides have advanced into clinical trials or have been approved by the FDA for use in patients. Among these fluorinated nucleosides, azvudine, developed by us, has been officially approved by the National Medical Products Administration for the treatment of coronavirus disease 2019 (COVID-19) and human immunodeficiency virus, indicating the therapeutic promise of fluorinated nucleosides.
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