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Updated: Jan 15, 2026
Generation of Escape Variants of Neutralizing Influenza Virus Monoclonal Antibodies
Published on: August 29, 2017
Optimization of VE607 to generate analogs with improved neutralization activities against SARS-CoV-2 variants
Shilei Ding1, Derek Yang2, Irfan Ullah3
1Centre de Recherche du CHUM, Montreal, Québec, Canada.
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.
Importance:
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-2WA1-challenged K18-hACE2 transgenic mice, suggesting that small-molecule compounds targeting viral entry might be useful in fighting evolving SARS-CoV-2 variants.
Insights
New small-molecule entry inhibitors targeting SARS-CoV-2 show enhanced potency against emerging variants like KP.3.1.1. These compounds, including DY-III-281, offer a promising strategy for combating evolving COVID-19 threats.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a significant threat, especially to vulnerable populations.
- Emerging omicron subvariants (e.g., KP.3.1.1, XEC) exhibit increased immune evasion capabilities.
- Existing vaccines and therapies face challenges due to viral evolution driven by Spike glycoprotein mutations.
Purpose of the Study:
- To develop novel small-molecule entry inhibitors with improved potency against SARS-CoV-2 variants.
- To characterize the efficacy of VE607 analogs against immune-evasive SARS-CoV-2 strains.
- To evaluate the therapeutic potential of lead compounds, alone and in combination with antibody therapies.
Main Methods:
- Generation and characterization of VE607 analogs targeting the SARS-CoV-2 Spike glycoprotein.
- In vitro assessment of inhibitory activity against emerging variants.
- In vivo studies using K18-hACE2 transgenic mice challenged with SARS-CoV-2.
- Evaluation of combination therapy with Fc-enhanced antibodies.
Main Results:
- Identified VE607 analogs with enhanced potency against SARS-CoV-2 variants, including KP.3.1.1 and XEC.
- The analog DY-III-281 demonstrated reduced viral burden and delayed mortality in a mouse model.
- Promising analogs stabilized the Spike glycoprotein's receptor-binding domain in the "up" conformation.
- Combination therapy of DY-III-281 with an Fc-enhanced antibody showed additive benefits in reducing disease burden.
Conclusions:
- Small-molecule entry inhibitors represent a viable strategy against evolving SARS-CoV-2 variants.
- DY-III-281 and similar compounds show promise as standalone or combination therapies.
- Continued development of these inhibitors is crucial for addressing future COVID-19 challenges.
