Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’.
No Thumbnail Available
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Chagas 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.
Description
Keywords
Small molecules, Cysteine protease inhibitors, Rhodesain, Cruzain
Citation
PEREIRA, 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.