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- W2176701219 abstract "The available drugs for the treatment of Chagas disease and leishmaniasisare not efficient and cause toxic side effects. Several studies show the possibility of drug resistance induction to Benznidazol (BZ) in Trypanosomacruzi, which may interfere with the treatmentefficacy. The same has been observed regarding compounds used to treat leishmaniasis, although more studies on drug resistance mechanism are needed. In the present study we focused on two potential drug resistance mechanisms: 1) P-glycoprotein (Pgp) activity, a membrane protein which acts as an efflux pump energy-dependentand isassociated with the multidrug resistance fenotype (MDR); 2) the enzyme nitroreductase (TcNTR) found in T. cruzi, which is responsible for the reduction of nitroheterocyclic derivatives, such as Bz and Nifurtimox, generating metabolites withtrypanocidal activity. In the search for new selective drugs for the treatment ofChagas disease and leishmaniasis, our group has been studying compounds from theclass of the thiosemicarbazones. Previous studies showed that the 4-N-(2-methoxy-styryl)-thiosemicarbazone (2-MEOTIO) was the most efficient compound on different forms of T.cruzi, whereas 4-N-(4’-hidroxy-3’-methoxy styryl)-thiosemicarbazone (3-MEOTIO) was the most active on Leishmania amazonensis. Here we evaluated the drug resistance mechanism to both thiosemicarbazone derivatives, as well as, to BZ which was used as reference drug for T. cruzi. Our results show the participation of Pgpin the resistance to both2-MEOTIO and BZ in T. cruzi,as well as in the resistance in L. amazonensisto the compound 3-MEOTIO. Interestingly, in T. cruzithe participation of Pgp is related to its localization not only in the plasma membrane but also in the mithocondrion. In addition, in T. cruzi, the loss of the TcNTRgene function is involved in BZ-resistance, however it was also shown that other mechanisms of drug resistanceare also involved and that that these mechanisms may be different even among clones obtained from a single population (B15). We also described here the in vitrovalidation of the expression of luciferase in different T. cruzistrainstransfectadedwith the red-shifted-luciferasegene,which will be further used in bioluminescence imaging assays in vivo. The drug resistance mechanisms in T. cruziand L. amazonensisshown here may be useful in the identification of parasite targets, aiming therational design of new drugs to treat for Chagas disease and leishmaniasis" @default.
- W2176701219 created "2016-06-24" @default.
- W2176701219 creator A5060696378 @default.
- W2176701219 date "2014-01-01" @default.
- W2176701219 modified "2023-09-27" @default.
- W2176701219 title "Estudo do mecanismo de resistência a compostos derivados da classe das tiossemicarbazonas em tripanosomatídeos, com ênfase na glicoproteína-P e na nitrorredutase do tipo I" @default.
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