Drugs can be targeted into African trypanosomes by exploiting
carrier proteins at the surface of these parasites. This has been clearly demonstrated in the case of the
melamine-based arsenical and the
diamidine classes of drug that are already in use in the treatment of human
African trypanosomiasis. These drugs can enter via an aminopurine transporter, termed P2, encoded by the TbAT1 gene. Other toxic compounds have also been designed to enter via this transporter. Some of these compounds enter almost exclusively through the P2 transporter, and hence loss of the P2 transporter leads to significant resistance to these particular compounds. It now appears, however, that some diamidines and melaminophenylarsenicals may also be taken up by other routes (of yet unknown function). These too may be exploited to target new drugs into trypanosomes. Additional
purine nucleoside and nucleobase transporters have also been subverted to deliver toxic agents to trypanosomes.
Glucose and
amino acid transporters too have been investigated with a view to manipulating them to carry toxins into Trypanosoma brucei, and recent work has demonstrated that
aquaglyceroporins may also have considerable potential for drug-targeting. Transporters, including those that carry
lipids and
vitamins such as
folate and other
pterins also deserve more attention in this regard. Some drugs, for example
suramin, appear to enter via routes other than plasma-membrane-mediated transport. Receptor-mediated endocytosis has been proposed as a possible way in for
suramin. Endocytosis also appears to be crucial in targeting natural
trypanocides, such as trypanosome lytic factor (TLF) (
apolipoprotein L1), into trypanosomes and this offers an alternative means of selectively targeting toxins to the trypanosome's interior. Other compounds may be induced to enter by increasing their capacity to diffuse over cell membranes; in this case depending exclusively on selective activity within the cell rather than selective uptake to impart selective toxicity. This review outlines studies that have aimed to exploit trypanosome nutrient uptake routes to selectively carry toxins into these parasites.