2. Academic Validation
  3. Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

  • Eur J Med Chem. 2025 Jun 21:297:117876. doi: 10.1016/j.ejmech.2025.117876.
Miguel M Vaidergorn 1,  Aline D Purificação 2,  Pedro I P Leite 3,  Sabrina Silva-Mendonça 4,  Wemenes J L Silva 4,  Thiago Dos Santos 3,  Daniel Gedder Silva 3,  Bruna Fleck Godoi 3,  Carolina Q Sacramento 5,  Mayara Mattos 5,  Natalia Fintelman-Rodrigues 5,  Caroline S Freitas 5,  Luis Eduardo Alves Damasceno 6,  Yoko Shishikura 7,  Alex Brown 7,  Karolina Wrobel 7,  Jennifer Riley 7,  Thiago M L Souza 5,  Kevin D Read 7,  José C Alves-Filho 6,  Carolina H Andrade 8,  M Cristina Nonato 9,  Flavio S Emery 10
Affiliations

Affiliations

  • 1 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Protein Crystallography Laboratory, Department of Biomolecular Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil.
  • 2 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Protein Crystallography Laboratory, Department of Biomolecular Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil.
  • 3 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil.
  • 4 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, 74605-170, GO, Brazil; Center for Excellence in Artificial Intelligence (CEIA), Institute of Informatics, Universidade Federal de Goiás, Goiânia, 74605-170, GO, Brazil.
  • 5 Laboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.
  • 6 Center of Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, 14040-900, Brazil.
  • 7 Drug Discovery Unit, University of Dundee, School of Life Sciences, Dow Street, Dundee, DD1 5EH, UK.
  • 8 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, 74605-170, GO, Brazil; Center for Excellence in Artificial Intelligence (CEIA), Institute of Informatics, Universidade Federal de Goiás, Goiânia, 74605-170, GO, Brazil. Electronic address: carolina@ufg.br.
  • 9 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Protein Crystallography Laboratory, Department of Biomolecular Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil. Electronic address: cristy@fcfrp.usp.br.
  • 10 Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil; Laboratory of Heterocyclic and Medicinal Chemistry (QHeteM), Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences at Ribeirao Preto, University of São Paulo, Ribeirão Preto, 14040-903, SP, Brazil. Electronic address: flavioemery@usp.br.
PMID: 40592187 DOI: 10.1016/j.ejmech.2025.117876
Abstract

In response to the rising challenge of pathogen resistance to anti-infective therapies, innovative approaches such as host-directed therapy are being investigated to bypass these resistance mechanisms. Dihydroorotate Dehydrogenase (DHODH) is a crucial enzyme for synthesizing pyrimidines, which are essential for RNA and DNA biosynthesis. Inhibiting DHODH can deplete the nucleotide pool, thereby impairing the replication of pathogens that depend on this pathway. In this study, we evaluated a library of fragment-like compounds against human DHODH (HsDHODH) and identified a 1,2-diarylethine scaffold as a potential new inhibitor. Utilizing the predicted binding mode and the activity of fragments 3a and 3l against HsDHODH, we designed and synthesized 14 novel diarylethine derivatives focused on improving their potency against the enzyme. The activity of the most potent compound (3e, IC50 1.50 ± 0.02 μM) was translated to Antiviral activity against SARS-CoV-2 in infected Calu-3 cells (EC50 1.7 ± 0.5 μM), with low cytotoxicity. Early ADME in vitro evaluation indicated a need for improved solubility, which will be addressed in subsequent multi-parameter optimization efforts. These findings pave the way for developing novel HsDHODH inhibitors with enhanced pharmacological and pharmacokinetics profiles, offering a promising strategy to address viral diseases that are resistant to conventional treatments.

Keywords

Antiviral activity; Diarylethines; Dihydroorotate dehydrogenase; Fragment-based drug discovery; Host-directed therapy; Human DHODH inhibitor; Structure-based drug discovery.

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