Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter

Sayé, Melisa; Fargnoli, Lucía; Reigada, Chantal; Labadié, Guillermo R.; Pereira, Claudio A.

doi:10.1016/j.bbagen.2017.08.015

“…Regarding proline transport as therapeutic target, to our knowledge there are no previous reports of drug repositioning although some proline analogues have been studied as trypanocidal compounds. For example, the proline analogue L-thiazolidine-4-carboxylic acid (T4C) has been reported as a proline transporter inhibitor with trypanocidal effect (55), and more recently, another proline analogue synthetized by rational design and called ITP-1G has been validated as a TcAAAP069 inhibitor that also possesses trypanocidal activity (25).…”

Section: Discussionmentioning

confidence: 99%

“…The aim was to obtain structurally related compounds which may have similar biological activity but with no (or less) toxicity toward the host cells since they are already in use to treat human diseases. The proline transporter TcAAAP069 was selected as the probable main target because: a) proline is a relevant amino acid for T. cruzi biology, including host cell invasion and life cycle progression (16,17), b) TcAAAP069 mediates proline uptake and it can also be used as a way of entry drugs into the parasite and, c) there is evidence of compounds that inhibit TcAAAP069 and also have trypanocidal activity, like the proline analogues T4C and ITP-1G (25,55).…”

Section: Discussionmentioning

confidence: 99%

“…The TcAAAP069 overexpressing parasites were available in our laboratory and were previously characterized (25). Briefly, TcAAAP069 (TriTrypDB ID: TcCLB.504069.120) was amplified using genomic T. cruzi DNA as template.…”

Section: Methodsmentioning

confidence: 99%

“…Since the transporter TcAAAP069 has many differential features compared to those present in mammals and proline is essential for parasite survival, it could be possible to design a specific inhibitor of this T. cruzi permease with trypanocidal action and non-toxic for the host cells. In fact, a synthetic proline analogue named ITP-1G has been validated as a TcAAAP069 inhibitor which also possesses trypanocidal effect (25). One of the best strategies for the identification of new treatments for neglected diseases is drug repositioning, which is the process of finding new indications for existing drugs.…”

Section: Introductionmentioning

confidence: 99%

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Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

¹

,

Gauna

²

,

Valera-Vera

³

et al. 2019

Preprint

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BackgroundCrystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069.Methodology/Principal FindingsCV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y strain. Additionally, loratadine, cyproheptadine and clofazimine showed trypanocidal effect on epimastigotes of the CL Brener and DM28c strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes of the Y strain.Conclusions/SignificanceLoratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.Author summaryChagas disease, caused by the parasite Trypanosoma cruzi, affects 7 million people worldwide. Despite there are two drugs available since 50 years ago, the therapy present severe side effects and is not effective in the chronic phase of the disease were most of the patients are diagnosed. Crystal violet (CV) was utilized as additive in blood banks to prevent transfusion-transmitted Chagas disease. Proline is involved in many pathways, like infection establishment and life cycle progression. In this work we first demonstrate that CV has the proline permease TcAAAP069 as one of its molecular targets. Then we search in a database of already-approved drugs for compounds that were structurally related to CV under the premise “similar structure, similar activity”. We identified three drugs that inhibit proline transport and present at least the same trypanocidal effect than benznidazole, the current treatment for Chagas disease. Finally we observed a synergistic effect with the multidrug combination therapy. Drug discovery is an expensive and time-consuming process and Chagas disease is associated with poverty. The discovery of new indications to old drugs, called drug repurposing, can facilitate a rapid and more profitable therapy application since preclinical trials and pharmacokinetic studies are already available.

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“…Since the transporter TcAAAP069 has many differential features compared to those present in mammals and proline is essential for parasite survival, it could be possible to design a specific TcAAAP069 inhibitor with trypanocidal action but non-toxic for the host cells. In fact, a synthetic proline analogue named ITP-1G has been validated as a TcAAAP069 inhibitor which also possesses trypanocidal effect [28]. One of the best strategies for the identification of new treatments for neglected diseases is drug repositioning, which is the process of finding new indications for existing drugs.…”

Section: Introductionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

¹

,

Gauna

²

,

Valera-Vera

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Crystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069. Methodology/Principal findings CV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y, CL Brener and Dm28c T. cruzi strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes and trypomastigotes of the Y strain. Conclusions/Significance Loratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages in strains from three different DTUs. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach,

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Amino Acid and Polyamine Membrane Transporters in Trypanosoma cruzi: Biological Function and Evaluation as Drug Targets

Sayé

¹

,

Reigada

²

,

Gauna

³

et al. 2019

CMC

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: Amino acids and polyamines are involved in relevant processes for the parasite Trypanosoma cruzi, like protein synthesis, stress resistance, life cycle progression, infection establishment and redox balance, among others. In addition to the biosynthetic routes of amino acids, T. cruzi possesses transport systems that allow the active uptake from the extracellular medium; and in the case of polyamines, the uptake is the unique way to obtain these compounds. The TcAAAP protein family is absent in mammals and its members are responsible for amino acid and derivative uptake, thus the TcAAAP permeases are not only interesting and promising therapeutic targets but could also be used to direct the entry of toxic compounds into the parasite. : Although there is a treatment available for Chagas disease, its limited efficacy in the chronic stage of the disease, as well as the side effects reported, highlight the urgent need to develop new therapies. Discovery of new drugs is a slow and cost-consuming process, and even during clinical trials the drugs can fail. In this context, drug repositioning is an interesting and recommended strategy by the World Health Organization since costs and time are significantly reduced. : In this article, amino acids and polyamines transport and their potential as therapeutic targets will be revised, including examples of synthetic drugs and drug repurposing.

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Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter

Cited by 9 publications

References 36 publications

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Amino Acid and Polyamine Membrane Transporters in Trypanosoma cruzi: Biological Function and Evaluation as Drug Targets

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