PreprintArticleVersion 1This version is not peer-reviewed
Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC
Version 1
: Received: 17 July 2024 / Approved: 17 July 2024 / Online: 17 July 2024 (13:12:49 CEST)
How to cite:
De Santis, A.; Grifagni, D.; Orsetti, A.; Lenci, E.; Rosato, A.; D'Onofrio, M.; Trabocchi, A.; Ciofi-Baffoni, S.; Cantini, F.; Calderone, V. Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC. Preprints2024, 2024071449. https://doi.org/10.20944/preprints202407.1449.v1
De Santis, A.; Grifagni, D.; Orsetti, A.; Lenci, E.; Rosato, A.; D'Onofrio, M.; Trabocchi, A.; Ciofi-Baffoni, S.; Cantini, F.; Calderone, V. Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC. Preprints 2024, 2024071449. https://doi.org/10.20944/preprints202407.1449.v1
De Santis, A.; Grifagni, D.; Orsetti, A.; Lenci, E.; Rosato, A.; D'Onofrio, M.; Trabocchi, A.; Ciofi-Baffoni, S.; Cantini, F.; Calderone, V. Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC. Preprints2024, 2024071449. https://doi.org/10.20944/preprints202407.1449.v1
APA Style
De Santis, A., Grifagni, D., Orsetti, A., Lenci, E., Rosato, A., D'Onofrio, M., Trabocchi, A., Ciofi-Baffoni, S., Cantini, F., & Calderone, V. (2024). Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC. Preprints. https://doi.org/10.20944/preprints202407.1449.v1
Chicago/Turabian Style
De Santis, A., Francesca Cantini and Vito Calderone. 2024 "Structural investigation of the interaction between a GC-376 based peptidomimetic PROTAC and the viral main protease of Coxsackievirus B3 to explore the applicability of a broad-spectrum antiviral PROTAC" Preprints. https://doi.org/10.20944/preprints202407.1449.v1
Abstract
The conservation of the main protease in viral genomes, combined with the absence of a homologous protease in humans, makes this enzyme family an ideal target for developing broad-spectrum antiviral drugs with minimal host toxicity. GC-376, a peptidomimetic 3CL protease inhibitor, has shown significant efficacy against coronaviruses. Recently, a GC-376-based PROTAC was developed to target and induce the proteosome-mediated degradation of the dimeric SARS-CoV-2 3CLPro protein. Extending this approach, the current study investigates the application of the GC-376 PROTAC to the 3CPro protease of Enteroviruses, specifically characterizing its interaction with CVB3 3CPro through X-ray crystallography, NMR and biophysical techniques. The present structural data show that there are some changes between the binding of CVB3 3CPro and SARS-CoV-2 3CLPro, but the overall similarity is strong. The most notable variation is the orientation of the phenylmethyl ester of GC-376 with the S4 subsite of the proteases. This is linked to the flexibility of the protein structure around the region of the catalytic triad shown by our NMR data. Other structural variations include distinct ligand interactions in subsites S1 and S2, influenced by the presence of Glu71 in CVB3 3CPro. Despite these differences, the GC-376 PROTAC fits well within the binding sites of both proteases, demonstrating its potential as a broad-spectrum antiviral agent.
Keywords
PROTAC; viral main protease; 3-Chymotrypsin-like protease; Coxsackievirus B3; SARS-CoV-2; GC-376
Subject
Biology and Life Sciences, Virology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
