Many of the recommended and experimental drugs that act on trypanosomatidae turn out to interfere with one or another reaction in the trypanothione pathway. This pathway leasd to the formation of trypanothione, an adduct of two molecules of glutathione linked to the two terminal amino groups of spermidine, that is formed from ornithine after decarboxylation. Although trypanosomatidae have no enzymes acting on glutathione such as glutathione reductase or glutathione peroxidase they have equivalent enzymes that act on trypanothione. Since trypanothione is in redox equilibrium with glutathione, the redox balance can be maintained. Most of the drugs shown in the scheme below increase the trypanosomatids sensitivity towards oxidative stress by a decrease in the level of reduced trypanothione. Either they inhibit the biosynthesis of trypanothione, or inhibit the reduction of its oxidized form, or they increase the cellular level of oxidative stress.
Eflornithine, difluoromethylornithine or DFMO is an irreversible inhibitor of the enzyme ornithine decarboxylase (1). Sinefungin is an inhibitor of the enzyme SAM decarboxylase (2) implicated in the conversion of putricine to spermidine. The active principle of the drug Mel B, or Arsobal, is melarsen oxide that has been shown to form an adduct with trypanothione. This complex behaves as a potent inhibitor of the enzyme trypanothione reductase, preventing the reduction of oxidized trypanothione. The other drugs indicated are known to be capable of redox cycling, leading to the production of superanion radicals, that lead to oxidative stress.
The notion that many different drugs all act on the sensitivity of the parasites towards oxidative stress has lead to the perception that combination therapy, using two or more drugs, may lead to synergism, resulting in a superior effect with lower dosages of the drugs than would otherwise be required.