From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability
The persistence of current outbreaks of Ebola virus (EBOV) disease and challenges in the production and administration of approved vaccines and treatments highlight the continuous exploration of new therapeutic alternatives. In this context, this work focuses on optimizing diarylsulfide hits previously identified as EBOV entry inhibitors. Structural modifications resulted in diarylamine derivatives, with confirmed antiviral activity against replicative EBOV and significantly improved metabolic stability compared to diarylsulfides. Using different techniques, the EBOV glycoprotein (EBOV-GP) was identified as the target of these compounds. Residue Y517<sub>GP2</sub> is critical for biological activity, while T519<sub>GP2</sub>, E100<sub>GP1</sub>, and D522<sub>GP2</sub> also contribute to ligand binding. Furthermore, the binding of the derivatives to EBOV-GP has been shown to destabilize the complex with the virus receptor NPC1. In short, a new family of diarylsulfides and diarylamines with antiviral activity against EBOV has been developed, and their mechanism of action has been deciphered, paving the way for future pharmaceutical development.
Authors
- Fátima Lasala (ORCID: https://orcid.org/0000-0001-8183-1866)
- Alfonso García‐Rubia
- Marcos Morales-Tenorio
- Michelle Heung
- Ángeles Canales (ORCID: https://orcid.org/0000-0003-0542-3080)
- Covadonga Alonso (ORCID: https://orcid.org/0000-0002-0862-6177)
- Ana Martı́nez (ORCID: https://orcid.org/0000-0002-2707-8110)
- Rafaël Delgado (ORCID: https://orcid.org/0000-0002-6912-4736)
- Catherine Olal (ORCID: https://orcid.org/0009-0006-2288-2026)
- Carmen Gil (ORCID: https://orcid.org/0000-0002-3882-6081)
- César Muñoz‐Fontela (ORCID: https://orcid.org/0000-0002-7725-2586)
- Elnaz Aledavood (ORCID: https://orcid.org/0000-0002-4837-7849)
- Beatriz Escudero-Pérez
- Paola Oquist
Institutions
- Universidad Complutense de Madrid (ES)
- Instituto de Salud Carlos III (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (ES)
- Centro de Investigación Biomédica en Red (ES)
- Centro de Investigaciones Biológicas Margarita Salas (ES)
- Indiana University School of Medicine
- Bernhard Nocht Institute for Tropical Medicine (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00615
- Citations
- 2
- Primary Topic
- Viral Infections and Outbreaks Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- “la Caixa” Foundation
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Horizon 2020 Framework Programme
- Consejo Superior de Investigaciones Científicas
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación