Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2017
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| _version_ | 1826307173514215424 |
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| author | Peres, RS Santos, GB Cecilio, NT Jabor, VAP Niehues, M Torres, BGS Buqui, G Silva, CHTP Costa, TD Lopes, NP Nonato, MC Ramalho, FS Louzada-Júnior, P Cunha, TM Cunha, FQ Emery, FS Alves-Filho, JC |
| author_facet | Peres, RS Santos, GB Cecilio, NT Jabor, VAP Niehues, M Torres, BGS Buqui, G Silva, CHTP Costa, TD Lopes, NP Nonato, MC Ramalho, FS Louzada-Júnior, P Cunha, TM Cunha, FQ Emery, FS Alves-Filho, JC |
| author_sort | Peres, RS |
| collection | OXFORD |
| description | 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.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.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.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. |
| first_indexed | 2024-03-07T06:58:57Z |
| format | Journal article |
| id | oxford-uuid:ff15470e-424a-4f51-9340-d3f5e03a282f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:58:57Z |
| publishDate | 2017 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:ff15470e-424a-4f51-9340-d3f5e03a282f2022-03-27T13:41:53ZLapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ff15470e-424a-4f51-9340-d3f5e03a282fEnglishSymplectic Elements at OxfordBioMed Central2017Peres, RSSantos, GBCecilio, NTJabor, VAPNiehues, MTorres, BGSBuqui, GSilva, CHTPCosta, TDLopes, NPNonato, MCRamalho, FSLouzada-Júnior, PCunha, TMCunha, FQEmery, FSAlves-Filho, JCThe 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.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.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.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. |
| spellingShingle | Peres, RS Santos, GB Cecilio, NT Jabor, VAP Niehues, M Torres, BGS Buqui, G Silva, CHTP Costa, TD Lopes, NP Nonato, MC Ramalho, FS Louzada-Júnior, P Cunha, TM Cunha, FQ Emery, FS Alves-Filho, JC Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title | Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title_full | Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title_fullStr | Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title_full_unstemmed | Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title_short | Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis |
| title_sort | lapachol a compound targeting pyrimidine metabolism ameliorates experimental autoimmune arthritis |
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