Unveiling novel pharmacophores and hit compounds for the development of anti-virals to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

  • Bioorg Chem. 2025 Jul 4:163:108724. doi: 10.1016/j.bioorg.2025.108724.
Belén Dávila  1 ,  Martín Fló  2 ,  Santiago Ruatta  3 ,  Franca Lorenzelli  3 ,  Andrea Medeiros  4 ,  Jonathan Bastidas  3 ,  Gonzalo Rodríguez  1 ,  Elena Aguilera  1 ,  María Fernanda García  5 ,  Angel H Romero  1 ,  Soonju Park  6 ,  Jinyeong Heo  6 ,  Honggun Lee  6 ,  Yeonguk Jeon  6 ,  Kyuho Paul Park  6 ,  David Shum  6 ,  Virginia López  7 ,  Marcos Couto  1 ,  Hugo Cerecetto  8 ,  Marcelo A Comini  3
Affiliations
  • 1. Grupo de Química Orgánica Medicinal, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
  • 2. Laboratorio de Inmunovirología, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay.
  • 3. Laboratorio de Biología Redox de Tripanosomas, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay.
  • 4. Laboratorio de Biología Redox de Tripanosomas, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay.
  • 5. Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
  • 6. Screening Platform, Institut Pasteur of Korea, 13488, South Korea.
  • 7. Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo 11800, Uruguay; Laboratorio de Biología Vascular y Desarrollo de Fármacos, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay.
  • 8. Grupo de Química Orgánica Medicinal, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay; Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay. Electronic address: [email protected].
PMID: 40639033 DOI: 10.1016/j.bioorg.2025.108724
Abstract

The respiratory Infection COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which continues to spread worldwide causing more than a million deaths yearly. Despite the rapid development of vaccines for prevention, a critical need remains for therapeutic agents to combat the established Infection. With this goal in mind, we conducted a target- (SARS-CoV-2 chemotrypsin-like Protease, MPro) and phenotypic-based screening of a subset of compounds from our in-house chemo-library. The selected compounds have been previously studied in different diseases' models. About 45 % of the analyzed compounds displayed inhibitory activity against MPro in the low μM range. Additionally, 3 out of 26 tested compounds (11 %) against SARS-CoV-2 displayed true anti-viral activity and (SI > 2). One of them belongs to the chloroquine-heterocycle chemotype, which was previously reported to hold anti-SARS-CoV-2. The remaining two novel hits belong to the polyhedral‑boron system, metallacarborane and dicarba-closo-dodecaborane chemotypes, which have not been previously reported for this anti-viral activity. In addition to targeting MPro, the chloroquine- and the metallacarborane-derivative, but not the dicarba-closo-dodecaborane, also inhibited the papain-like Protease of SARS-CoV-2.

Keywords
Anti-viral activity; Bis(arylidenyl)ketone derivatives; COVID-19; Polyhedral boron derivatives; Protease inhibitor; SARS-CoV-2.
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