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

ABSTRACT: Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is a prominent paradigm in drug discovery. In this study, we applied conventional and novel PROTAC approaches to develop broad-spectrum antivirals (targeting key host factors for many different viruses) and virus-specific antivirals (targeting unique viral proteins). With respect to host-directed antivirals, we identified a small molecule degrader, FM-74-103, with pan-antiviral activities, as shown by inhibiting both RNA and DNA viruses. FM-74-103 elicits the selective degradation of human GSPT1, a translation termination factor, which further shuts down translation initiation. With respect to virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). We provided proof-ofprinciple that RNA mimics of viral promoter sequences can be used as molecular glues to recruit viral polymerase (vPOL) and target it for degradation. Collectively, this study shows that TPD can be exploited to rationally design and develop the next generations of antivirals.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung Epithelial Cell Differentiation

DISEASE(S): Covid-19,Influenza

SUBMITTER: Jeffrey Johnson

LAB HEAD: Jeffrey R Johnson

PROVIDER: PXD042352 | Pride | 2023-06-15

REPOSITORIES: Pride

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

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