EDITORIAL: Old Drugs × New Perspectives/New Compounds × Old Necessities: Focusing on Combating Microbial Resistance – Part I

Santos, André Luis Souza dos; Kneipp, Lucimar F.; d’Avila-Levy, Claudia M.; Sodré, Cátia Lacerda; Branquinha, Marta H.

doi:10.2174/156802661710170214192825

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“…However, there is no direct evidence on the functional role of the aspartyl peptidases in these parasites, such as knockout or RNA interference approaches. Nevertheless, we and others have demonstrated that HIV-PIs exert potent antiparasitic effects in vitro on Leishmania promastigotes and intracellular amastigotes, but the exact biochemical target and mechanism of action is still poorly understood (Savoia et al , 2005 ; Trudel et al , 2008 ; Santos et al , 2009 , 2013 a ; Valdivieso et al , 2010 ; van Griensven et al , 2013 ; White et al , 2011 ; Demarchi et al , 2012 for a comprehensive review see Santos et al , 2013 b , 2017 ). Transmission electron microscopy (TEM) revealed that HIV-PIs provoke an increase in lipid inclusions in Leishmania amazonensis (Santos et al , 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism ofLeishmania amazonensispromastigotes

et al. 2018

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The anti-leishmania effects of HIV peptidase inhibitors (PIs) have been widely reported; however, the biochemical target and mode of action are still a matter of controversy in Leishmania parasites. Considering the possibility that HIV-PIs induce lipid accumulation in Leishmania amazonensis, we analysed the effects of lopinavir on the lipid metabolism of L. amazonensis promastigotes. To this end, parasites were treated with lopinavir at different concentrations and analysed by fluorescence microscopy and spectrofluorimetry, using a fluorescent lipophilic marker. Then, the cellular ultrastructure of treated and control parasites was analysed by transmission electron microscopy (TEM), and the lipid composition was investigated by thin-layer chromatography (TLC). Finally, the sterol content was assayed by gas chromatography–mass spectrometry (GC/MS). TEM analysis revealed an increased number of lipid inclusions in lopinavir-treated cells, which was accompanied by an increase in the lipophilic content, in a dose-dependent manner. TLC and GC–MS analysis revealed a marked increase of cholesterol-esters and cholesterol. In conclusion, lopinavir-induced lipid accumulation and affected lipid composition in L. amazonensis in a concentration–response manner. These data contribute to a better understanding of the possible mechanisms of action of this HIV-PI in L. amazonensis promastigotes. The concerted action of lopinavir on this and other cellular processes, such as the direct inhibition of an aspartyl peptidase, may be responsible for the arrested development of the parasite.

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Section: Introductionmentioning

confidence: 99%

Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism ofLeishmania amazonensispromastigotes

et al. 2018

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Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase

et al. 2018

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ObjectiveThe low investment in research, diagnosis and treatment are factors that contribute to the continuity of Chagas’ disease as a neglected tropical diseases (NTDs). In this context, the repositioning of drugs represents a useful strategy, in the search for new chemotherapeutic approaches for NTDs. HIV aspartic peptidase inhibitors (HIV IPs) are good candidates for drug repurposing. Here, we modeled the three dimensional structure of an aspartyl peptidase of Trypanosoma cruzi, the causative agent of Chagas’ disease, aligned it to the HIV aspartyl peptidase and performed docking binding assays with the HIV PIs.ResultsThe 3D structure confirmed the presence of acid aspartic residues, which are critical to enzyme activity. The docking experiment revealed that HIV IPs bind to the active site of the enzyme, being ritonavir and lopinavir the ones with greater affinity. Benznidazole presented the worst binding affinity, this drug is currently used in Chagas’ disease treatment and was included as negative control. These results together with previous data on the trypanocidal effect of the HIV PIs support the hypothesis that a T. cruzi aspartyl peptidase can be the intracellular target of these inhibitors. However, the direct demonstration of the inhibition of T. cruzi aspartyl peptidase activity by HIV PIs is still a goal to be persuaded.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3927-z) contains supplementary material, which is available to authorized users.

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EDITORIAL: Old Drugs × New Perspectives/New Compounds × Old Necessities: Focusing on Combating Microbial Resistance – Part I

Cited by 2 publications

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Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism ofLeishmania amazonensispromastigotes

Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism ofLeishmania amazonensispromastigotes

Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase

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