M P Barrett

..These results indicate that the ability of trypanosomes to use proline as an energy source can be regulated depending upon the availability of glucose...

..We conclude that trypanosomes develop an elaborate adaptation of their energy production pathways in response to carbon source availability...

..Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease...

..Growth in recognition of these neglected diseases might result in progress towards control through increased funding for drug development and vector elimination...

..Here we discuss recent developments in metabolomic analysis, from the perspective of trypanosome research, highlighting remaining challenges and the most promising areas for future research...

..Therefore we also discuss approaches to designing molecules that can specifically cross the plasma membrane of African trypanosomes via unusual nutrient transporters...

..Here, Mike Barrett and Alan Fairlamb outline the mechanism underlying this crossresistance, which appears to arise as a result of alterations in an unusual adenosine transporter involved in the uptake of these drugs...

..The equilibration phase represented a simple passive diffusion, with the subsequent uptake probably being due to metabolism of the drug...

..Recent mutagenesis studies of sugar transporters within the framework of tenable models for the distantly related lactose permease argue that this model is a good paradigm for other members of the major facilitator superfamily...

..New drugs are urgently needed and the advent of genome sequencing and target validation using genetic modification will hopefully accelerate this process...

..Subtle distinctions in the function of these proteins can be related to particular amino acid residue substitutions...

..In the rodent malaria P. chabaudi, transcription of members of the gene family was developmentally regulated with maximum expression in late trophozoite stages, which is the developmental stage known to express variant antigen proteins...

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..We conclude that TbAT1 mediates [(3)H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates...

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..b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells...

..This review focuses on what is known about modes of action of current drugs and discusses targets for future drug development...

..In tsetse flies, however, it seems probable that the effect of GlcNAc is independent of this switch as pre-adaptation to growth in proline had no effect on tsetse infection rate...

..The influence of environmental pH on membrane transporter function is discussed, with emphasis on the potential role of a transmembrane proton gradient in active, high affinity transport...

..Genome survey sequencing in P. chabaudi is a productive strategy in further developing this in vivo model of malaria, in the context of the malaria genome projects...

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..The two DNA-containing structures in the trypanosome--the nucleus and the kinetoplast--begin to fluoresce within 1 min of introduction of DB99, unless drug resistant...

..brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles...

..Pfprex is the first example of a gene encoding contiguous DNA polymerase, DNA primase and DNA helicase components. We propose it has a key role in replication of the malarial plastid genome, a validated drug target...

..This review outlines studies that have aimed to exploit trypanosome nutrient uptake routes to selectively carry toxins into these parasites...

..Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosomes...

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..Trypanocidal activity was evident, but compounds were equally toxic against trypanosomes lacking the P2 transporter, which indicates additional uptake routes for monobenzamidine-derived compounds...

..These studies indicate that prex is conserved across the plastid-bearing apicomplexans and may play an important role in the replication of the plastid genome...

..Several compounds showed significant in vitro activity and were selectively active against the parasites over human embryonic kidney cells used as a counter screen...

..Parasites resistant to megazol were selected and showed modest cross-resistance to other trypanocides, although neither drug efflux nor changes to intracellular thiols correlated with resistance...

..Expression of TbNBT1 in Xenopus oocytes further confirmed that this gene encodes the first high affinity nucleobase transporter from protozoa or animals to be identified at the molecular level...

..The location of these residues in hydrophilic loops supports recent suggestions that substrate recognition is separated from substrate binding and translocation in this important group of transporters...

..The aza analogues of DB75 accumulate more slowly than furamidine itself and reveal less trypanocidal activity in standard in vitro drug sensitivity assays...

..Transketolase is thus the first enzyme of the nonoxidative branch of the pentose phosphate pathway whose presence has been demonstrated in a peroxisome-like organelle...

..These results establish that each glucose transporter isoform has distinct biological functions in the parasite...

..Preliminary testing of the biological activity of the compounds revealed significant anti-parasitic activity against bloodstream form African trypanosomes...

..In this article, we summarize how these recent data have helped to change the view of metabolism in procyclic-form T. brucei...

..High-level arsenical resistance therefore appears to involve the loss of more than one transporter...

..The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani)...

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..In addition, pan-African initiatives to co-ordinate control efforts have begun. These all provide some hope for the future, but they might not be enough to reverse the resurgence of this deadly disease in the heart of Africa...

..Financial constraints continue to represent a major hurdle to drug development. However, the appearance of not-for-profit product-development partnerships offers a new paradigm for bringing new drugs to patients...

..LlPDH can now serve as a model system for structure-based inhibitor design targeting the enzyme from Trypanosoma species...

..The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T. brucei 6PGDH with a Ki in the nanomolar range...

..cruzi against which various nitro heterocycles are already registered for use...

..Most prodrugs caused inhibition of the growth of the parasites. The activity of the prodrugs against the parasites appeared to be related to their stability in aqueous buffer...

..From these studies, the 4,4'-diaminodiphenylamine skeleton emerged as a good scaffold for antitrypanosomal drugs...

..All have shown selective inhibition of the trypanosomal 6-phosphogluconate dehydrogenase and representatives of each have trypanocidal activity...

..Data integration will play a particularly important part in exploiting the new experimental opportunities...

..The enzyme product ribose 5-phosphate inhibited the phosphorylation of D-ribose with an apparent K(i) of 0.4 mM, which is close to the K(m) (0.3 mM) of D-ribose, suggesting that it might play a role in regulating flux through the enzyme...

..This indicates that inhibition of the transporter may be a good means of killing trypanosomes...

..One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both blood and mosquito stages, and against blood-stage Trypanosoma brucei brucei...