Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin)
Leishmaniasis, caused by protozoa of the genus <i>Leishmania</i>, encompasses a group of neglected diseases with diverse clinical and epidemiological manifestations that can be fatal if not adequately and promptly managed/treated. The current chemotherapy options for this disease are exp...
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MDPI AG
2023-06-01
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| Series: | Tropical Medicine and Infectious Disease |
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| Online Access: | https://www.mdpi.com/2414-6366/8/7/348 |
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| author | Simone S. C. Oliveira Claudyane A. Correia Vanessa S. Santos Elaine F. F. da Cunha Alexandre A. de Castro Teodorico C. Ramalho Michael Devereux Malachy McCann Marta H. Branquinha André L. S. Santos |
| author_facet | Simone S. C. Oliveira Claudyane A. Correia Vanessa S. Santos Elaine F. F. da Cunha Alexandre A. de Castro Teodorico C. Ramalho Michael Devereux Malachy McCann Marta H. Branquinha André L. S. Santos |
| author_sort | Simone S. C. Oliveira |
| collection | DOAJ |
| description | Leishmaniasis, caused by protozoa of the genus <i>Leishmania</i>, encompasses a group of neglected diseases with diverse clinical and epidemiological manifestations that can be fatal if not adequately and promptly managed/treated. The current chemotherapy options for this disease are expensive, require invasive administration and often lead to severe side effects. In this regard, our research group has previously reported the potent anti-<i>Leishmania</i> activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)<sub>3</sub>].(ClO<sub>4</sub>)<sub>2</sub>.4H<sub>2</sub>O and [Ag(phendione)<sub>2</sub>].ClO<sub>4</sub>. The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all <i>Leishmania</i> species that plays multiple functions and is recognized as a potential target for antiparasitic drugs. The results showed that both Ag-phendione (−74.82 kcal/mol) and Cu-phendione (−68.16 kcal/mol) were capable of interacting with the amino acids comprising the active site of the gp63 protein, exhibiting more favorable interaction energies compared to phendione alone (−39.75 kcal/mol) or 1,10-phenanthroline (−45.83 kcal/mol; a classical gp63 inhibitor) as judged by molecular docking assay. The analysis of kinetic parameters using the fluorogenic substrate Z-Phe-Arg-AMC indicated V<sub>max</sub> and apparent K<sub>m</sub> values of 0.064 µM/s and 14.18 µM, respectively, for the released gp63. The effects of both complexes on gp63 proteolytic activity were consistent with the in silico assay, where Ag-phendione exhibited the highest gp63 inhibition capacity against gp63, with an IC<sub>50</sub> value of 2.16 µM and the lowest inhibitory constant value (K<sub>i</sub> = 5.13 µM), followed by Cu-phendione (IC<sub>50</sub> = 163 µM and K<sub>i</sub> = 27.05 µM). Notably, pretreatment of live <i>L. amazonensis</i> promastigotes with the complexes resulted in a significant reduction in the expression of gp63 protein, including the isoforms located on the parasite cell surface. Both complexes markedly decreased the in vitro association indexes between <i>L. amazonensis</i> promastigotes and THP-1 human macrophages; however, this effect was reversed by the addition of soluble gp63 molecules to the interaction medium. Collectively, our findings highlight the potential use of these potent complexes in antivirulence therapy against <i>Leishmania</i>, offering new insights for the development of effective treatments for leishmaniasis. |
| first_indexed | 2024-03-11T00:35:13Z |
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| issn | 2414-6366 |
| language | English |
| last_indexed | 2024-03-11T00:35:13Z |
| publishDate | 2023-06-01 |
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| series | Tropical Medicine and Infectious Disease |
| spelling | doaj.art-6d78d366ea264f1cacf83dd39bd6d1e82023-11-18T21:38:57ZengMDPI AGTropical Medicine and Infectious Disease2414-63662023-06-018734810.3390/tropicalmed8070348Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin)Simone S. C. Oliveira0Claudyane A. Correia1Vanessa S. Santos2Elaine F. F. da Cunha3Alexandre A. de Castro4Teodorico C. Ramalho5Michael Devereux6Malachy McCann7Marta H. Branquinha8André L. S. Santos9Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, BrazilLaboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, BrazilLaboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, BrazilLaboratório de Modelagem Molecular, Departamento de Química, Universidade Federal de Lavras, Lavras 37200-000, BrazilLaboratório de Modelagem Molecular, Departamento de Química, Universidade Federal de Lavras, Lavras 37200-000, BrazilLaboratório de Modelagem Molecular, Departamento de Química, Universidade Federal de Lavras, Lavras 37200-000, BrazilThe Centre for Biomimetic & Therapeutic Research, Focas Research Institute, Technological University Dublin, D08 CKP1 Dublin, IrelandChemistry Department, Maynooth University, W23 F2H6 Maynooth, IrelandLaboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, BrazilLaboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, BrazilLeishmaniasis, caused by protozoa of the genus <i>Leishmania</i>, encompasses a group of neglected diseases with diverse clinical and epidemiological manifestations that can be fatal if not adequately and promptly managed/treated. The current chemotherapy options for this disease are expensive, require invasive administration and often lead to severe side effects. In this regard, our research group has previously reported the potent anti-<i>Leishmania</i> activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)<sub>3</sub>].(ClO<sub>4</sub>)<sub>2</sub>.4H<sub>2</sub>O and [Ag(phendione)<sub>2</sub>].ClO<sub>4</sub>. The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all <i>Leishmania</i> species that plays multiple functions and is recognized as a potential target for antiparasitic drugs. The results showed that both Ag-phendione (−74.82 kcal/mol) and Cu-phendione (−68.16 kcal/mol) were capable of interacting with the amino acids comprising the active site of the gp63 protein, exhibiting more favorable interaction energies compared to phendione alone (−39.75 kcal/mol) or 1,10-phenanthroline (−45.83 kcal/mol; a classical gp63 inhibitor) as judged by molecular docking assay. The analysis of kinetic parameters using the fluorogenic substrate Z-Phe-Arg-AMC indicated V<sub>max</sub> and apparent K<sub>m</sub> values of 0.064 µM/s and 14.18 µM, respectively, for the released gp63. The effects of both complexes on gp63 proteolytic activity were consistent with the in silico assay, where Ag-phendione exhibited the highest gp63 inhibition capacity against gp63, with an IC<sub>50</sub> value of 2.16 µM and the lowest inhibitory constant value (K<sub>i</sub> = 5.13 µM), followed by Cu-phendione (IC<sub>50</sub> = 163 µM and K<sub>i</sub> = 27.05 µM). Notably, pretreatment of live <i>L. amazonensis</i> promastigotes with the complexes resulted in a significant reduction in the expression of gp63 protein, including the isoforms located on the parasite cell surface. Both complexes markedly decreased the in vitro association indexes between <i>L. amazonensis</i> promastigotes and THP-1 human macrophages; however, this effect was reversed by the addition of soluble gp63 molecules to the interaction medium. Collectively, our findings highlight the potential use of these potent complexes in antivirulence therapy against <i>Leishmania</i>, offering new insights for the development of effective treatments for leishmaniasis.https://www.mdpi.com/2414-6366/8/7/348<i>Leishmania amazonensis</i>alternative chemotherapyantivirulence strategycoordination compoundsgp63virulence |
| spellingShingle | Simone S. C. Oliveira Claudyane A. Correia Vanessa S. Santos Elaine F. F. da Cunha Alexandre A. de Castro Teodorico C. Ramalho Michael Devereux Malachy McCann Marta H. Branquinha André L. S. Santos Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) Tropical Medicine and Infectious Disease <i>Leishmania amazonensis</i> alternative chemotherapy antivirulence strategy coordination compounds gp63 virulence |
| title | Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) |
| title_full | Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) |
| title_fullStr | Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) |
| title_full_unstemmed | Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) |
| title_short | Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against <i>Leishmania</i>: Focus on Gp63 (Leishmanolysin) |
| title_sort | silver i and copper ii 1 10 phenanthroline 5 6 dione complexes as promising antivirulence strategy against i leishmania i focus on gp63 leishmanolysin |
| topic | <i>Leishmania amazonensis</i> alternative chemotherapy antivirulence strategy coordination compounds gp63 virulence |
| url | https://www.mdpi.com/2414-6366/8/7/348 |
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