Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics

  • Cell Host Microbe. 2023 Jul 12;31(7):1154-1169.e10. doi: 10.1016/j.chom.2023.05.030.
Nan Zhao  1 ,  Jessica Sook Yuin Ho  2 ,  Fanye Meng  3 ,  Simin Zheng  2 ,  Andrew P Kurland  2 ,  Lu Tian  4 ,  Martha Rea-Moreno  5 ,  Xiangyang Song  3 ,  Ji-Seon Seo  6 ,  H Ümit Kaniskan  3 ,  Aartjan J W Te Velthuis  7 ,  Domenico Tortorella  2 ,  Ya-Wen Chen  8 ,  Jeffrey R Johnson  2 ,  Jian Jin  9 ,  Ivan Marazzi  10
Affiliations
  • 1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4. Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5. Department of Otolaryngology, Master of Science in Biomedical Science Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 6. Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 7. Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 8. Department of Otolaryngology, Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 9. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
  • 10. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: [email protected].
PMID: 37339625 DOI: 10.1016/j.chom.2023.05.030
Abstract

Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 Ligase ligand, recruit a target protein to the E3 Ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique Viral Proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.

Keywords
CMV; GSPT1; PROTAC; SARS-CoV-2; antiviral therapeutics; influenza virus; oligonucleotide; small molecule.
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