Design and synthesis of a series of truncated neplanocin fleximers.

In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC50 values around 200 μM.

Apicoplast lipoic acid protein ligase B is not essential for Plasmodium falciparum.

Lipoic acid (LA) is an essential cofactor of alpha-keto acid dehydrogenase complexes (KADHs) and the glycine cleavage system. In Plasmodium, LA is attached to the KADHs by organelle-specific lipoylation pathways. Biosynthesis of LA exclusively occurs in the apicoplast, comprising octanoyl-[acyl carrier protein]: protein N-octanoyltransferase (LipB) and LA synthase.

Molecular interactions underlying the unusually high adenosine affinity of a novel Trypanosoma brucei nucleoside transporter.

Trypanosoma brucei encodes a relatively high number of genes of the equilibrative nucleoside transporter (ENT) family. We report here the cloning and in-depth characterization of one T. brucei brucei ENT member, TbNT9/AT-D.

The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in african trypanosomes.

Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [(3)H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms.

Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei.

Sleeping sickness, caused by Trypanosoma brucei spp., has become resurgent in sub-Saharan Africa. Moreover, there is an alarming increase in treatment failures with melarsoprol, the principal agent used against late-stage sleeping sickness.

Cloning, heterologous expression, and in situ characterization of the first high affinity nucleobase transporter from a protozoan.

While multiple nucleoside transporters, some of which can also transport nucleobases, have been cloned in recent years from many different organisms, no sequence information is available for the high affinity, nucleobase-selective transporters of metazoa, parazoa, or protozoa. We have identified a gene, TbNBT1, from Trypanosoma brucei brucei that encodes a 435-residue protein of the equilibrative nucleoside transporter superfamily. The gene was expressed in both the procyclic and bloodstream forms of the organism.

A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter.

Nucleobase transporters play an important role in the physiology of protozoan parasites, because these organisms are purine auxotrophs and rely entirely on salvage of these vital compounds. Purine transporters have also been shown to mediate the uptake of important antiparasitic drugs. In the current study, we investigated the uptake of [(3)H]adenine, [(3)H]hypoxanthine, and [(3)H]allopurinol, an antileishmanial hypoxanthine analog, by Leishmania major.

Different substrate recognition motifs of human and trypanosome nucleobase transporters. Selective uptake of purine antimetabolites.

The therapeutic index of antimetabolites such as purine analogues is in large part determined by the extent to which it is selectively accumulated by the target cell. In the current study we have compared the transport of purine nucleobase analogues by the H2 transporter of bloodstream form Trypanosoma brucei brucei and the equilibrative nucleobase transporter of human erythrocytes. The H2 transporter forms hydrogen bonds with hypoxanthine at positions N3, N7, N(1)H, and N(9)H of the purine ring, with apparent Delta G(0) of 7.