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Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.
Hagey, Rachel J; Elazar, Menashe; Pham, Edward A; Tian, Siqi; Ben-Avi, Lily; Bernardin-Souibgui, Claire; Yee, Matthew F; Moreira, Fernando R; Rabinovitch, Meirav Vilan; Meganck, Rita M; Fram, Benjamin; Beck, Aimee; Gibson, Scott A; Lam, Grace; Devera, Josephine; Kladwang, Wipapat; Nguyen, Khanh; Xiong, Anming; Schaffert, Steven; Avisar, Talia; Liu, Ping; Rustagi, Arjun; Fichtenbaum, Carl J; Pang, Phillip S; Khatri, Purvesh; Tseng, Chien-Te; Taubenberger, Jeffery K; Blish, Catherine A; Hurst, Brett L; Sheahan, Timothy P; Das, Rhiju; Glenn, Jeffrey S.
  • Hagey RJ; ViRx@Stanford, Stanford Medicine, Stanford, CA, USA.
  • Elazar M; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • Pham EA; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Tian S; ViRx@Stanford, Stanford Medicine, Stanford, CA, USA.
  • Ben-Avi L; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Bernardin-Souibgui C; ViRx@Stanford, Stanford Medicine, Stanford, CA, USA.
  • Yee MF; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Moreira FR; Department of Biochemistry, Stanford University, Stanford, CA, USA.
  • Rabinovitch MV; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Meganck RM; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Fram B; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Beck A; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Gibson SA; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Lam G; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Devera J; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Kladwang W; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Nguyen K; Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA.
  • Xiong A; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Schaffert S; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Avisar T; Department of Biochemistry, Stanford University, Stanford, CA, USA.
  • Liu P; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Rustagi A; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Fichtenbaum CJ; Department of Medicine, Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA.
  • Pang PS; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Khatri P; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Tseng CT; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Taubenberger JK; Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • Blish CA; Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Hurst BL; Department of Medicine, Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA.
  • Sheahan TP; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Das R; Center for Biodefense and Emerging Diseases, Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA.
  • Glenn JS; Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Med ; 28(9): 1944-1955, 2022 09.
Article in English | MEDLINE | ID: covidwho-1991643
ABSTRACT
Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term 'programmable antivirals', with implications for antiviral prophylaxis and post-exposure therapy.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Influenza A virus / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Vaccines / Variants Limits: Animals Language: English Journal: Nat Med Journal subject: Molecular Biology / Medicine Year: 2022 Document Type: Article Affiliation country: S41591-022-01908-x

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Influenza A virus / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Vaccines / Variants Limits: Animals Language: English Journal: Nat Med Journal subject: Molecular Biology / Medicine Year: 2022 Document Type: Article Affiliation country: S41591-022-01908-x