Discovery of Thiophene Derivatives as Potent, Orally Bioavailable, and Blood–Brain Barrier-Permeable Ebola Virus Entry Inhibitors
The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.
Authors
- Beatriz Escudero-Pérez (ORCID: https://orcid.org/0000-0003-3655-0525)
- Fátima Lasala (ORCID: https://orcid.org/0000-0001-8183-1866)
- Alfonso García‐Rubia
- Marcos Morales-Tenorio
- Michelle Heung
- 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)
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 Investigaciones Biológicas Margarita Salas (ES)
- Bernhard Nocht Institute for Tropical Medicine (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01267
- Citations
- 7
- Primary Topic
- Viral Infections and Outbreaks Research
- Type
- article
- Field-Weighted Citation Impact
- 2.72
Funders
- “la Caixa” Foundation
- European Commission
- Ministerio de Ciencia e Innovación
- Horizon 2020 Framework Programme
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación