Journal Article

Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2

Pham, Edward A., Xiong, Anming, Nguyen, Khanh, Moreira, Fernando R., Fram, Benjamin, Lam, Grace, Meganck, Rita M., Khatri, Purvesh, Sheahan, Timothy P., Das, Rhiju, Gibson, Scott A., Taubenberger, Jeffery K., Ben-Avi, Lily, Beck, Aimee, Avisar, Talia, Fichtenbaum, Carl J., Liu, Ping, Schaffert, Steven, Glenn, Jeffrey S., Hurst, Brett L., Tian, Siqi, Kladwang, Wipapat, Bernardin-Souibgui, Claire, Rabinovitch, Meirav Vilan, Rustagi, Arjun, Hagey, Rachel J., Yee, Matthew F., Tseng, Chien-Te, Blish, Catherine A., Elazar, Menashe, Devera, Josephine, Pang, Phillip S.

2022

Overview

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. Targeting conserved secondary structure of RNA viruses offers the potential for a customizable therapeutic approach to viral variants.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/326/596/1578 / 631/326/596/4130 / Animals / Antiviral agents / Antiviral Agents - pharmacology / Antiviral drugs / Biomedical and Life Sciences / Biomedicine / Cancer Research / COVID-19 / COVID-19 Drug Treatment / Disease resistance / Drug development / Drug resistance / Exo-a-sialidase / Genomes / Hamsters / Infectious Diseases / Influenza / Influenza A / Influenza A virus - genetics / Inoculum / Metabolic Diseases / Mice / Molecular Medicine / Mutation / Neuraminidase / Neurosciences / Nucleic acids / Packaging / Prophylaxis / Protein structure / Ribonucleic acid / RNA / RNA viruses / RNA, Viral - genetics / SARS-CoV-2 / Secondary structure / Severe acute respiratory syndrome coronavirus 2 / Therapeutic targets / Viral diseases / Viruses