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

Author(s):Show less -

Peres, Raphael S. ; Santos, Gabriela B. ; Cecilio, Nerry T. ; Jabor, Valquria A. P. ; Niehues, Michael ; Torres, Bruna G. S. ; Buqui, Gabriela ; Silva, Carlos H. T. P. ; Dalla Costa, Teresa ; Lopes, Norberto P. ; Nonato, Maria C. ; Ramalho, Fernando S. ; Louzada-Junior, Paulo ; Cunha, Thiago M. ; Cunha, Fernando Q. ; Emery, Flavio S. ; Alves-Filho, Jose C.

• Document type: Journal article
• Source: ARTHRITIS RESEARCH & THERAPY; v. 19, MAR 7 2017.
• Web of Science Citations: 6

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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/20990-2 - Antiinfective compounds: an evolution in the medicinal chemistry of leishmanicidal tiazoles and the search for new tuberculostic agents
• Grantee: Flavio da Silva Emery
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/54014-7 - Acquisition of a biophotonic imaging system and a multiphoton microscopy system for in vivo imaging
• Grantee: Enilza Maria Espreafico
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 12/25075-0 - Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
• Grantee: Norberto Peporine Lopes
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants