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

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

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: hcerecet@fq.edu.uy.
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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