Abstract
Despite the available drug options, leishmaniasis treatment remains unsatisfactory. The repurposing of calpain inhibitors originally developed for human diseases became an interesting alternative, since Leishmania cells express calpain-related proteins. The susceptibility of six Leishmania species (L. amazonensis, L. braziliensis, L. major, L. mexicana, L. chagasi, and L. donovani) to the calpain inhibitor MDL28170 was determined. Promastigote and intracellular amastigote viability in the presence of MDL28170 was evaluated. MDL28170 was able to reduce promastigote proliferation in a dose-dependent manner for all the parasites. A significant reduction on the general parasite metabolism was detected, as judged by resazurin assay, as well as induced important morphological alterations, including rounding promastigotes and loss of the flagellum. MDL28170 was also able to reduce the number of intracellular amastigotes in RAW macrophages. The susceptibility of both parasite stages (promastigotes and amastigotes) to MDL28170 was similar for all Leishmania species tested. MDL28170 showed a much higher toxicity to Leishmania amastigotes when compared with mammalian macrophages, displaying selectivity index values varying from 13.1 to 39.8. These results suggest that the development of calpain inhibitors may represent an interesting alternative in the treatment of leishmaniasis.
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Acknowledgments
The authors would like to thank Denise Rocha de Souza, who is supported by a FAPERJ scholarship, for her technical assistance.
Funding
This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação Oswaldo Cruz (FIOCRUZ). ALSS, MHB, and CMd’A-L were supported by CNPq and FAPERJ fellowships.
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Section Editor: Sarah Hendrickx
André Luis Souza dos Santos and Marta Helena Branquinha share senior authorship.
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de Sousa Araújo, P.S., de Oliveira, S.S.C., d’Avila-Levy, C.M. et al. Susceptibility of promastigotes and intracellular amastigotes from distinct Leishmania species to the calpain inhibitor MDL28170. Parasitol Res 117, 2085–2094 (2018). https://doi.org/10.1007/s00436-018-5894-7
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DOI: https://doi.org/10.1007/s00436-018-5894-7