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Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)

Leishmaniasis, caused by protozoa of the genus Leishmania, 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 inv...

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Autores principales: Oliveira, Simone S. C., Correia, Claudyane A., Santos, Vanessa S., da Cunha, Elaine F. F., de Castro, Alexandre A., Ramalho, Teodorico C., Devereux, Michael, McCann, Malachy, Branquinha, Marta H., Santos, André L. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10384183/
https://www.ncbi.nlm.nih.gov/pubmed/37505644
http://dx.doi.org/10.3390/tropicalmed8070348
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author Oliveira, Simone S. C.
Correia, Claudyane A.
Santos, Vanessa S.
da Cunha, Elaine F. F.
de Castro, Alexandre A.
Ramalho, Teodorico C.
Devereux, Michael
McCann, Malachy
Branquinha, Marta H.
Santos, André L. S.
author_facet Oliveira, Simone S. C.
Correia, Claudyane A.
Santos, Vanessa S.
da Cunha, Elaine F. F.
de Castro, Alexandre A.
Ramalho, Teodorico C.
Devereux, Michael
McCann, Malachy
Branquinha, Marta H.
Santos, André L. S.
author_sort Oliveira, Simone S. C.
collection PubMed
description Leishmaniasis, caused by protozoa of the genus Leishmania, 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-Leishmania activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)(3)].(ClO(4))(2).4H(2)O and [Ag(phendione)(2)].ClO(4). The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all Leishmania 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(max) and apparent K(m) 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(50) value of 2.16 µM and the lowest inhibitory constant value (K(i) = 5.13 µM), followed by Cu-phendione (IC(50) = 163 µM and K(i) = 27.05 µM). Notably, pretreatment of live L. amazonensis 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 L. amazonensis 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 Leishmania, offering new insights for the development of effective treatments for leishmaniasis.
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spelling pubmed-103841832023-07-30 Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin) Oliveira, Simone S. C. Correia, Claudyane A. Santos, Vanessa S. da Cunha, Elaine F. F. de Castro, Alexandre A. Ramalho, Teodorico C. Devereux, Michael McCann, Malachy Branquinha, Marta H. Santos, André L. S. Trop Med Infect Dis Article Leishmaniasis, caused by protozoa of the genus Leishmania, 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-Leishmania activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)(3)].(ClO(4))(2).4H(2)O and [Ag(phendione)(2)].ClO(4). The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all Leishmania 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(max) and apparent K(m) 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(50) value of 2.16 µM and the lowest inhibitory constant value (K(i) = 5.13 µM), followed by Cu-phendione (IC(50) = 163 µM and K(i) = 27.05 µM). Notably, pretreatment of live L. amazonensis 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 L. amazonensis 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 Leishmania, offering new insights for the development of effective treatments for leishmaniasis. MDPI 2023-06-30 /pmc/articles/PMC10384183/ /pubmed/37505644 http://dx.doi.org/10.3390/tropicalmed8070348 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Oliveira, Simone S. C.
Correia, Claudyane A.
Santos, Vanessa S.
da Cunha, Elaine F. F.
de Castro, Alexandre A.
Ramalho, Teodorico C.
Devereux, Michael
McCann, Malachy
Branquinha, Marta H.
Santos, André L. S.
Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title_full Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title_fullStr Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title_full_unstemmed Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title_short Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin)
title_sort silver(i) and copper(ii) 1,10-phenanthroline-5,6-dione complexes as promising antivirulence strategy against leishmania: focus on gp63 (leishmanolysin)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10384183/
https://www.ncbi.nlm.nih.gov/pubmed/37505644
http://dx.doi.org/10.3390/tropicalmed8070348
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