2016
DOI: 10.1371/journal.ppat.1005436
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Pentamidine Is Not a Permeant but a Nanomolar Inhibitor of the Trypanosoma brucei Aquaglyceroporin-2

Abstract: The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and most widely used drugs is pentamidine, an aromatic diamidine compound introduced in the 1940s. Recently, a genome-wide loss-of-function screen and a subsequently generated trypanosome knockout strain revealed a specific aquaglyceroporin, TbAQP2, to be required for high-affinity uptake of pentamidine. Yet, the underlying mechanism remained uncl… Show more

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Cited by 49 publications
(71 citation statements)
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“…Formate molecules in FocA crystals at low, that is, physiological, substrate concentration have been found next to the lysine (Wang et al, 2009;Lü et al, 2011) despite a very low apparent affinity (Lü et al, 2012a). Low, channel-like substrate affinities clearly distinguish FNTs from classical transporters, for example, of the alternating access type, which can be seen as a protection against inhibition (Song et al, 2016) by abundant anions with slow transport rates, such as chloride (Lü et al, 2012a). The proton motive force dependency of FNTs, however, is a typical feature of secondary transporters.…”
Section: Discussionmentioning
confidence: 99%
“…Formate molecules in FocA crystals at low, that is, physiological, substrate concentration have been found next to the lysine (Wang et al, 2009;Lü et al, 2011) despite a very low apparent affinity (Lü et al, 2012a). Low, channel-like substrate affinities clearly distinguish FNTs from classical transporters, for example, of the alternating access type, which can be seen as a protection against inhibition (Song et al, 2016) by abundant anions with slow transport rates, such as chloride (Lü et al, 2012a). The proton motive force dependency of FNTs, however, is a typical feature of secondary transporters.…”
Section: Discussionmentioning
confidence: 99%
“…The HAPT1/ Tb AQP2 carrier (De Koning, 2001 b ), encoded by the TbAQP2 gene (Baker et al 2012), has a key role in uptake of pentamidine and the melaminophenyl arsenicals in T. brucei , although its role in diminazene uptake is less pronounced (Teka et al 2011; Munday et al 2014) and loss of P2/ Tb AT1 alone is sufficient to give high level of resistance to this latter drug (Matovu et al 2003). It has recently been proposed that Tb AQP2 acts as a receptor for pentamidine, with high affinity, and its uptake then occurs via receptor-mediated endocytosis (Song et al 2016); further work is needed to confirm or refute this hypothesis, although other evidence points to pentamidine actually entering through the channel, enabled by a unique selectivity filter and the high degree of flexibility of the pentamidine chain (Munday et al 2014, 2015 a ). …”
Section: Veterinary Trypanocides: Dosage Pharmacokinetics Mode Of Amentioning
confidence: 99%
“…These changes are expected to enlarge the pore size and thus allow passage of cations, including the highly flexible pentamidine molecule [36]. However, an alternative model, in which AQP2 binds pentamidine and mediates internalization via receptor-mediated endocytosis, was recently proposed [48 •• ]. This is an attractive alternative, marrying the implausibility of large-molecule transport by TbAQP2, an unusually high affinity for pentamidine, the high endocytosis of bloodstream trypanosomes [12 • ] and localization of TbAQP2 to the flagellar pocket [44 • ].…”
Section: Old and Still In The Clinic: Pentamidine And Melarsoprolmentioning
confidence: 99%