Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’.

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dc.contributor.authorPereira, Glaécia Aparecida do Nascimento
dc.contributor.authorSilva, Elany Barbosa da
dc.contributor.authorBraga, Saulo Fehelberg Pinto
dc.contributor.authorLeite, Paulo Gaio
dc.contributor.authorMartins, Luan Carvalho
dc.contributor.authorVieira, Rafael Pinto
dc.contributor.authorSoh, Wai Tuck
dc.contributor.authorVillela, Filipe Silva
dc.contributor.authorCosta, Francielly Morais Rodrigues da
dc.contributor.authorRay, Debalina
dc.contributor.authorAndrade, Saulo Fernandes de
dc.contributor.authorBrandstetter, Hans
dc.contributor.authorOliveira, Renata Barbosa
dc.contributor.authorCaffrey, Conor R.
dc.contributor.authorMachado, Fabiana Simão
dc.contributor.authorFerreira, Rafaela Salgado
dc.date.accessioned2022-12-07T19:54:34Z
dc.date.available2022-12-07T19:54:34Z
dc.date.issued2019pt_BR
dc.description.abstractChagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 mM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain in- hibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 mM. Therefore, through a combi- nation of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.pt_BR
dc.identifier.citationPEREIRA, G. A. N. et al. Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’. European Journal of Medicinal Chemistry, v. 179, p. 765-778, 2019. Disponível em: <https://www.sciencedirect.com/science/article/pii/S0223523419305896>. Acesso em: 11 out. 2022.pt_BR
dc.identifier.doihttps://doi.org/10.1016/j.ejmech.2019.06.062pt_BR
dc.identifier.issn0223-5234
dc.identifier.urihttp://www.repositorio.ufop.br/jspui/handle/123456789/15875
dc.identifier.uri2https://www.sciencedirect.com/science/article/pii/S0223523419305896pt_BR
dc.language.isoen_USpt_BR
dc.rightsrestritopt_BR
dc.subjectSmall moleculespt_BR
dc.subjectCysteine protease inhibitorspt_BR
dc.subjectRhodesainpt_BR
dc.subjectCruzainpt_BR
dc.titleDiscovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’.pt_BR
dc.typeArtigo publicado em periodicopt_BR
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