In vitro activity of crystal violet structural analogues for drug repositioning against trypanosomatid parasites

PEREIRA, CA; SAYE, MELISA; REIGADA, CHANTAL; DIDWANIA, N; ALI, N

Congreso; XXXVI Meeting of the Brazilian Society of Protozoology; 2021

Brazilian Society of Protozoology

Trypanosoma cruzi, the causative agent of Chagas disease, uses proline (Pro) as main carbon source when glucose is not available. Pro is also involved in many essential biological processes, such as differentiation and cellular invasion. We have reported that the permease TcAAAP069 mediates Pro uptake and it is involved in T. cruzi survival. AAAP transporters family is present in all trypanosomatid parasites and is low represented in mammals. Recently, we have validated TcAAAP069 as one of the targets of crystal violet (CV), a compound used for several years in blood banks to eliminate T. cruzi, and then we applied a virtual screening approach in order to identify drugs approved for clinical use that might have similar effects to CV. The antihistamines loratadine and cyproheptadine; and the antibiotic clofazimine inhibited Pro transport and had trypanocidal effect with IC50 values between 1 and 13 μM in trypomastigotes and amastigotes.We also evaluated the antiparasitic effects of the drugs in Trypanosoma brucei and Leishmania donovani, the causative agents of human African trypanosomiasis and visceral leishmaniasis, respectively. All mentioned CV analogues presented activity against T. brucei procyclic trypomastigotes and L. donovani promastigotes, with IC50 values between 1 and 44 μM. Moreover, preliminary tests on L. donovani with cationic liposomal formulations of the drugs showed that drug-loaded liposomes had a higher leishmanicidal activity than free compounds. LdAAP24 and TbAAT6 are the orthologous genes of TcAAAP069 in Leishmania and T. brucei, therefore the Pro transport inhibition of CV analogues will be evaluated as possible mechanism of action of such drugs.In conclusion, CV structural analogues are promising anti-trypanosomatid compounds, in addition to being approved drugs used in humans, known as repurposed drugs, which could significantly reduce the requirements for its possible application in the treatment of neglected diseases.