2015
DOI: 10.1128/aac.00596-15
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Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy

Abstract: The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing grou… Show more

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Cited by 18 publications
(18 citation statements)
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“…Here we tested a number of pyrimidine nucleoside analogs for inhibition of LmajNT1 and found that 5F-Urd and 5F-2′dUrd, in particular, but also 4-thiouridine and 5F-5′dUrd were able to inhibit this transporter. Using these and other results, we were able to construct a model for pyrimidine nucleoside binding by LmajNT1, which should assist in the further selection of possible substrates for this carrier, much as it has done for some of the T. brucei transporters for which we constructed similar models (Lüscher et al., 2007b, Chollet et al., 2009, Vodnala et al., 2013, Rodenko et al., 2015). …”
Section: Discussionmentioning
confidence: 99%
“…Here we tested a number of pyrimidine nucleoside analogs for inhibition of LmajNT1 and found that 5F-Urd and 5F-2′dUrd, in particular, but also 4-thiouridine and 5F-5′dUrd were able to inhibit this transporter. Using these and other results, we were able to construct a model for pyrimidine nucleoside binding by LmajNT1, which should assist in the further selection of possible substrates for this carrier, much as it has done for some of the T. brucei transporters for which we constructed similar models (Lüscher et al., 2007b, Chollet et al., 2009, Vodnala et al., 2013, Rodenko et al., 2015). …”
Section: Discussionmentioning
confidence: 99%
“…The aforementioned screening was performed using T. brucei cells harvested from mammalian hosts. The lead compound was taken up by transporter H2 with higher affinity than its typical substrates—adenine and hypoxanthine (Rodenko et al, ). Yeast could thus be a valuable instrument to accelerate primary drug screening.…”
Section: Applications Of Purine Auxotrophic Yeastmentioning
confidence: 99%
“…DNA fragmentation after exposure of T. brucei bloodstream forms (Lister 427) to FANA-A (with or without dCF) was determined as described previously (54). Drug-free and phleomycin (Sigma)-treated cells were used as negative and positive controls, respectively.…”
Section: Methodsmentioning
confidence: 99%