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

Nan Zhao, Jessica Sook Yuin Ho, Fanye Meng, Simin Zheng, Andrew P. Kurland, Lu Tian, Martha Rea-Moreno, Xiangyang Song, Ji Seon Seo, H. Ümit Kaniskan, Aartjan J.W. te Velthuis, Domenico Tortorella, Ya Wen Chen, Jeffrey R. Johnson, Jian Jin, Ivan Marazzi

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1154-1169.e10
JournalCell Host and Microbe
Volume31
Issue number7
DOIs
StatePublished - Jul 12 2023

All Science Journal Classification (ASJC) codes

  • Virology
  • Parasitology
  • Microbiology

Keywords

  • CMV
  • GSPT1
  • PROTAC
  • SARS-CoV-2
  • antiviral therapeutics
  • influenza virus
  • oligonucleotide
  • small molecule

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