NSP7 Molecular Degrader Attenuates Coronaviral Infection Through the β-TrCP1/FBXO5 Axis

Yao Tong; Travis B Lear; Ferhan Tuncer; John J Villandre; Áine N Boudreau; Bo Lin; Irene Alfaras; Jason R Kennerdell; Daniel P Camarco; Mads B Larsen; Yun Hua; Yanwen Chen; Meigin E Chandler; Ricardo Pineda; Simon M Barratt-Boyes; John W Evankovich; Toren Finkel; Yuan Liu; Bill B Chen

doi:10.1002/advs.202500798

NSP7 Molecular Degrader Attenuates Coronaviral Infection Through the β-TrCP1/FBXO5 Axis

Adv Sci (Weinh). 2025 Jun 27:e00798. doi: 10.1002/advs.202500798. Online ahead of print.

Authors

Yao Tong¹, Travis B Lear¹, Ferhan Tuncer¹, John J Villandre¹, Áine N Boudreau¹, Bo Lin¹, Irene Alfaras¹, Jason R Kennerdell¹, Daniel P Camarco¹, Mads B Larsen¹, Yun Hua¹, Yanwen Chen¹, Meigin E Chandler¹, Ricardo Pineda², Simon M Barratt-Boyes³, John W Evankovich^{1

2}, Toren Finkel^{1

4}, Yuan Liu^{1

2}, Bill B Chen^{1

2}

Affiliations

¹ Aging Institute, University of Pittsburgh/UPMC, Pittsburgh, PA, 15219, USA.
² Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
³ Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁴ Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

PMID: 40577599
DOI: 10.1002/advs.202500798

Abstract

NSP7 (Non-Structural Protein 7) of SARS-CoV-2 is a crucial component for viral replication and transcription. In this study, it is revealed that the host E3 ubiquitin ligase FBXO5 suppresses viral replication by mediating NSP7 lysine-48-linked ubiquitination and subsequent proteasomal degradation. Interestingly, it is also determined that NSP7 expression impairs the host antiviral response by inhibiting the ISGylation of melanoma differentiation-associated protein 5 (MDA5), a key sensor for viral RNA. Through an unbiased esiRNA screen, it is identified that NSP7 ubiquitination is coregulated by β-TrCP1 and the kinase TAF1. Additionally, this study uncovers a small molecule FBXO5 stabilizer that disrupts the β-TrCP1-FBXO5 interaction, thereby markedly enhancing NSP7 degradation and effectively mitigating SARS-CoV-2 infection. Taken together, the findings reveal a novel mechanism for NSP7 regulation and suggest that small-molecule activators of the E3 ubiquitin ligase FBXO5 represent a promising new class of host-directed antiviral therapies.

Keywords: FBXO5; TAF1; antiviral therapies; non‐structural protein 7; ubiquitination; β‐TrCP1.

Abstract

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