2. Academic Validation
  3. From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability

From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability

  • J Med Chem. 2025 Jun 12;68(11):11786-11800. doi: 10.1021/acs.jmedchem.5c00615.
Marcos Morales-Tenorio 1,  Fátima Lasala 2,  Alfonso Garcia-Rubia 1,  Elnaz Aledavood 1,  Michelle Heung 3,  Catherine Olal 3,  Beatriz Escudero-Pérez 3,  Paola Oquist 4,  Ángeles Canales 4,  Covadonga Alonso 5,  Ana Martínez 1 6,  César Muñoz-Fontela 3,  Rafael Delgado 2 7 8,  Carmen Gil 1 6
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), 28040 Madrid, Spain.
  • 2 Instituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain.
  • 3 Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
  • 4 Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain.
  • 5 Dpt. Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA-CSIC), 28040 Madrid, Spain.
  • 6 CIBERNED, Instituto Salud Carlos III, 28029 Madrid, Spain.
  • 7 CIBERINFEC, Instituto Salud Carlos III, 28029 Madrid, Spain.
  • 8 School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain.
PMID: 40381209 DOI: 10.1021/acs.jmedchem.5c00615
Abstract

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 Y517GP2 is critical for biological activity, while T519GP2, E100GP1, and D522GP2 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.

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