Journal article
Optimization of VE607 to generate analogs with improved neutralization activities against SARS-CoV-2 variants
Journal of virology, v 99(11), e0103425
25 Nov 2025
PMID: 41081594
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a threat to human health, particularly among immunocompromised and elderly individuals, given their heightened vulnerability to coronavirus disease 2019 (COVID-19)-associated morbidity and mortality. Recently, omicron subvariants such as KP.3.1.1 and XEC have emerged with an enhanced ability to evade humoral immunity. The development of new strategies against these variants of concern remains an intense area of research. The small molecule VE607 is an entry inhibitor that targets the Spike glycoprotein and delays virus spread in vivo. To improve the potency of this new class of SARS-CoV-2 entry inhibitors, we generated and characterized VE607 analogs and identified candidates with enhanced activity against variants, including KP.3.1.1 and XEC. Promising analogs exhibited higher inhibitory potency than the original compound and stabilized the receptor-binding domain in its “up” conformation. Among these, DY-III-281 also reduced viral burden and delayed death in SARS-CoV-2-challenged K18-hACE2 transgenic mice. Furthermore, combining DY-III-281 with a non-neutralizing antibody engineered for Fc-enhanced functions exhibited an additive effect in reducing SARS-CoV-2-induced disease burden in mice. Our findings support the continued development of small-molecule entry inhibitors, alone or in combination with antibody-based therapies, as a promising strategy to counteract emerging SARS-CoV-2 variants.IMPORTANCEMutations 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-2WA1-challenged K18-hACE2 transgenic mice, suggesting that small-molecule compounds targeting viral entry might be useful in fighting evolving SARS-CoV-2 variants.
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Details
- Title
- Optimization of VE607 to generate analogs with improved neutralization activities against SARS-CoV-2 variants
- Creators
- Shilei Ding - ,Derek Yang - University of PennsylvaniaIrfan Ullah - Yale UniversityLing Niu - Uniformed Services University of the Health SciencesMatthew Unger - University of Massachusetts Chan Medical SchoolMarco A. Díaz-Salinas - University of Massachusetts Chan Medical SchoolMonika Chandravanshi - Uniformed Services University of the Health SciencesFei Zhou - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentGuillaume Beaudoin-Bussières - Université de MontréalMehdi Benlarbi - Université de MontréalWilliam D. Tolbert - Uniformed Services University of the Health SciencesKeon-Woong Yoon - Yale UniversityRuixue Xu - Yale UniversityGeneviève Laroche - University of OttawaFleur Gaudette - ,Abraham J. Morton - National Cancer InstituteZabrina C. Lang - National Cancer InstituteAnna Son - University of PennsylvaniaCameron Abrams - Drexel UniversityMarceline Côté - University of OttawaAmos B. Smith - University of PennsylvaniaRick K. Huang - National Cancer InstituteDoreen Matthies - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentJames B. Munro - University of Massachusetts Chan Medical SchoolMarzena Pazgier - Uniformed Services University of the Health SciencesPradeep D. Uchil - Yale UniversityAndrés Finzi - Université de Montréal
- Contributors
- Shan-Lu Liu (Editor)
- Publication Details
- Journal of virology, v 99(11), e0103425
- Publisher
- American Society for Microbiology
- Number of pages
- 34
- Grant note
- 41027 / Exceptional Fund COVID-19 from the Canada Foundation for Innovation Z1A / Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH HD008998 / Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH 487578 / CIHR operating RN497587-494246 / Canadian Institutes of Health Research (http://dx.doi.org/10.13039/501100000024) 177958 / CIHR operating Pandemic and Health Emergencies Research FBD-193357 / Canadian Institutes of Health Research (http://dx.doi.org/10.13039/501100000024) R01AI163395 / National Institutes of Health (http://dx.doi.org/10.13039/100000002) R01GM143773 / National Institutes of Health (http://dx.doi.org/10.13039/100000002) R24OD026440-03S1 / National Institutes of Health (http://dx.doi.org/10.13039/100000002)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:001591647700001
- Scopus ID
- 2-s2.0-105022796093
- Other Identifier
- 991022197304204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology