Optimization of VE607 to generate analogs with improved neutralization activities against SARS-CoV-2 variants
Mutations in the Spike glycoprotein drive viral evolution and confer resistance to current vaccines and some therapeutic interventions against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report new analogs of the SARS-CoV-2 small-molecule entry inhibitor VE607. These analogs exhibited improved potency against emerging SARS-CoV-2 variants, including KP.3.1.1 and XEC. One analog, DY-III-281, delayed viral replication in SARS-CoV-2<sub>WA1</sub>-challenged K18-hACE2 transgenic mice, suggesting that small-molecule compounds targeting viral entry might be useful in fighting evolving SARS-CoV-2 variants.
Authors
- Rick Huang (ORCID: https://orcid.org/0000-0002-3336-9635)
- Guillaume Beaudoin-Bussières (ORCID: https://orcid.org/0000-0002-8092-4101)
- Doreen Matthies (ORCID: https://orcid.org/0000-0001-9221-4484)
- Fei Zhou (ORCID: https://orcid.org/0000-0001-6657-7433)
- Mehdi Benlarbi (ORCID: https://orcid.org/0000-0001-9966-3784)
- Pradeep D. Uchil (ORCID: https://orcid.org/0000-0002-7236-858X)
- Monika Chandravanshi (ORCID: https://orcid.org/0000-0003-3049-4649)
- Cameron F. Abrams (ORCID: https://orcid.org/0000-0002-1240-0816)
- James B. Munro (ORCID: https://orcid.org/0000-0001-7634-4633)
- Marzena Pazgier (ORCID: https://orcid.org/0000-0003-0594-5057)
- Fleur Gaudette (ORCID: https://orcid.org/0000-0003-0453-1522)
- Andrés Finzi (ORCID: https://orcid.org/0000-0002-4992-5288)
- Keon-Woong Yoon
- Aseom Son (ORCID: https://orcid.org/0000-0002-6110-8790)
- Zabrina C. Lang
- William D. Tolbert (ORCID: https://orcid.org/0000-0001-7549-9596)
- Derek Yang (ORCID: https://orcid.org/0000-0001-8959-384X)
- Marceline Côté (ORCID: https://orcid.org/0000-0002-4664-4325)
- Amos B. Smith (ORCID: https://orcid.org/0000-0002-1712-8567)
- Geneviève Laroche (ORCID: https://orcid.org/0000-0002-5979-6344)
- Ling Niu (ORCID: https://orcid.org/0000-0001-7512-0865)
- Marco A. Díaz-Salinas (ORCID: https://orcid.org/0000-0003-2983-0123)
- Irfan Ullah (ORCID: https://orcid.org/0000-0003-1100-101X)
- Shilei Ding (ORCID: https://orcid.org/0000-0003-1895-5131)
- Ruixue Xu
- A. Morton (ORCID: https://orcid.org/0009-0006-7278-6227)
- Matthew Unger
Institutions
- Uniformed Services University of the Health Sciences (US)
- University of Ottawa (CA)
- University of Massachusetts Chan Medical School (US)
- Yale University (US)
- Biological E (India) (IN)
- National Cancer Institute (MY)
- National Cancer Institute (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- UMass Memorial Medical Center (US)
- Institute of Infection and Immunity (CA)
- Université de Montréal (CA)
- Drexel University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Journal of Virology
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1128/jvi.01034-25
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00