Transporters in Anti‐Parasitic Drug Development and Resistance

Delespaux, V.; Koning, Harry P. de

doi:10.1002/9783527670383.ch18

Cited by 16 publications

(17 citation statements)

References 84 publications

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“…Given that CpdA is quite lipophilic, it is expected to diffuse rather than be transported across the plasma membrane, so that uptake-related resistance is not possible, in contrast to actively accumulated trypanocidal drug classes like the diamidines (51). Importantly, no cross-resistance was observed with the current trypanosomiasis drugs, including diamidines, arsenicals, suramin, and nifurtimox, showing that PDE inhibitors have a distinct mechanism of resistance.…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA

Gould

Bachmaier

Ali

et al. 2013

Antimicrob Agents Chemother

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One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.

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Section: Discussionmentioning

confidence: 99%

Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA

Gould

Bachmaier

Ali

et al. 2013

Antimicrob Agents Chemother

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“…Current trypanocidal drugs have a number of limitations such as high rate of toxicity, low rate of efficacy, and drug resistance (2,3). Therefore, it is important to look for a drug that is effective and does not produce harmful side effects.…”

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confidence: 99%

“…2 Recipient of FQRNT Fellowship 134790. 3 Recipient of a Lloyd Carr-Harris fellowship (McGill University). 4 To whom correspondence should be addressed.…”

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confidence: 99%

Naphthalene-based RNA Editing Inhibitor Blocks RNA Editing Activities and Editosome Assembly in Trypanosoma brucei

Moshiri

Acoca

Kala

et al. 2011

Journal of Biological Chemistry

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RNA editing, catalyzed by the multiprotein editosome complex, is an essential step for the expression of most mitochondrial genes in trypanosomatid pathogens. It has been shown previously that Trypanosoma brucei RNA editing ligase 1 (TbREL1), a core catalytic component of the editosome, is essential in the mammalian life stage of these parasitic pathogens. Because of the availability of its crystal structure and absence from human, the adenylylation domain of TbREL1 has recently become the focus of several studies for designing inhibitors that target its adenylylation pocket. Here, we have studied new and existing inhibitors of TbREL1 to better understand their mechanism of action. We found that these compounds are moderate to weak inhibitors of adenylylation of TbREL1 and in fact enhance adenylylation at higher concentrations of protein. Nevertheless, they can efficiently block deadenylylation of TbREL1 in the editosome and, consequently, result in inhibition of the ligation step of RNA editing. Further experiments directly showed that the studied compounds inhibit the interaction of the editosome with substrate RNA. This was supported by the observation that not only the ligation activity of TbREL1 but also the activities of other editosome proteins such as endoribonuclease, terminal RNA uridylyltransferase, and uridylate-specific exoribonuclease, all of which require the interaction of the editosome with the substrate RNA, are efficiently inhibited by these compounds. In addition, we found that these compounds can interfere with the integrity and/or assembly of the editosome complex, opening the exciting possibility of using them to study the mechanism of assembly of the editosome components.Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major are three major trypanosomatid pathogens that cause hundreds of thousands of deaths and infect millions of people in tropical and subtropical areas of the world (1). Current trypanocidal drugs have a number of limitations such as high rate of toxicity, low rate of efficacy, and drug resistance (2, 3). Therefore, it is important to look for a drug that is effective and does not produce harmful side effects. RNA editing is a unique posttranscriptional modification of mitochondrial mRNAs that is shared in all trypanosomatid pathogens (4, 5). Modification of specific editing sites, dictated by complementary guide RNAs (gRNAs), 5 constitutes essential steps to ensure the production of translatable mRNAs that encode essential components of the mitochondrial respiratory system. Although gRNAs specify the number of uridylates (Us) to be added or deleted by base pairing at each editing block (6, 7), a 1.6-MDa multiprotein complex, the editosome, is responsible for catalysis of different steps of RNA editing. Although the complete composition of the editosome is being elucidated, most purified functional editosomes contain over 20 proteins (8,9). The editosomes differ in their compositions, having at least three different complexes that sediment at ϳ20 S on glycerol gradie...

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“…Di-tert-butyl 2-((4-(4-((1,3-bis(tert-butoxycarbonyl)imidazolidin-2-ylidene)amino)-2-chlorobenzamido)phenyl)imino)imidazolidine-1,3-dicarboxylate (30 4.1.6.3. Di-tert-butyl 2-((4-((4-((1,3-bis(tert-butoxycarbonyl)imidazolidin-2-ylidene)amino)-2-chlorophenyl)carbamoyl)phenyl)imino)imidazolidine-1,3-dicarboxylate (31).…”

Section: Methods D: General Procedures For the Reduction Of 4-nitrobenzmentioning

confidence: 99%

“…class, it is likely that the large difference in time-to-kill reflects differences in uptake rate, mediated by an as yet unidentified transport protein or mechanism [30].…”

Section: Cmpdmentioning

confidence: 99%

Lowering the p K a of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

Martinez

Martínez

Ebiloma

et al. 2015

European Journal of Medicinal Chemistry

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Transporters in Anti‐Parasitic Drug Development and Resistance

Cited by 16 publications

References 84 publications

Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA

Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA

Naphthalene-based RNA Editing Inhibitor Blocks RNA Editing Activities and Editosome Assembly in Trypanosoma brucei

Lowering the p K a of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

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