2. Academic Validation
  3. Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis

Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis

  • Arthritis Res Ther. 2017 Mar 7;19(1):47. doi: 10.1186/s13075-017-1236-x.
Raphael S Peres 1,  Gabriela B Santos 2,  Nerry T Cecilio 1,  Valquíria A P Jabor 3,  Michael Niehues 3,  Bruna G S Torres 4,  Gabriela Buqui 3,  Carlos H T P Silva 2,  Teresa Dalla Costa 4,  Norberto P Lopes 3,  Maria C Nonato 3,  Fernando S Ramalho 5,  Paulo Louzada-Júnior 6,  Thiago M Cunha 1,  Fernando Q Cunha 1,  Flavio S Emery 7,  Jose C Alves-Filho 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Ribeirão Preto Medical School, Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, CEP: 14049-900, Brazil.
  • 2 Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, Ribeirão Preto, CEP: 14040-903, Brazil.
  • 3 NPPNS, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, Ribeirão Preto, Brazil.
  • 4 Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Sarmento Leite 521, Porto Alegre, Brazil.
  • 5 Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, Brazil.
  • 6 Department of Internal Medicine, Ribeirão Preto Medical School, Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, Brazil.
  • 7 Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, Ribeirão Preto, CEP: 14040-903, Brazil. [email protected].
  • 8 Department of Pharmacology, Ribeirão Preto Medical School, Center of Research in Inflammatory Diseases (CRID), University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo, CEP: 14049-900, Brazil. [email protected].
PMID: 28270195 DOI: 10.1186/s13075-017-1236-x
Abstract

Background: The inhibition of pyrimidine biosynthesis by blocking the Dihydroorotate Dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties.

Methods: Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP.

Results: We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation.

Conclusions: Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.

Keywords

Collagen-induced arthritis; DMARDs; Dihydroorotate dehydrogenase; Inflammation; Lapachol; Pyrimidine metabolism; Rheumatoid arthritis.

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