Polyamine Metabolism: A Potential Therapeutic Target in Trypanosomes

Abstract

alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…An analysis of the period showed that cases of HAT occurred significantly more often in settings with political turmoil and internationalized civil war, with a 10-year interval between onset of conflict and peak prevalence (132). By the 1990s, epidemic disease had returned to central Africa (113,130,133,134). By 1995, the reported annual number of cases of gambiense HAT had reached levels not seen for half a century, which was particularly alarming because only a small fraction of the areas at risk were under surveillance, and the true magnitude of the epidemic was unknown.…”

“…Surveillance for gambiense HAT decreased and was curtailed in many areas as public health authorities in the newly independent countries turned their attention and resources to other priorities. In addition, conflicts and insecurity constrained disease control interventions (130,131). An analysis of the period showed that cases of HAT occurred significantly more often in settings with political turmoil and internationalized civil war, with a 10-year interval between onset of conflict and peak prevalence (132).…”

“…In order to further avoid nonspecific reactions and to standardize and facilitate the test production process, the possibility of replacing the native proteins used as antigens in these tests by recombinant proteins or synthetic peptides is being investigated (24,129). The development of the LAMP assay represents important progress and, if the format is simplified further, could bring molecular diagnostics closer to the district or reference hospital level (13,130). Studies are ongoing to determine the diagnostic accuracy of LAMP in clinical samples, and its impact and cost-efficacy relative to the standard parasitological tests in order to support its implementation (26,67).…”

Biothérapies, immunothérapies, thérapies ciblées, biomédicaments…

“…Son utilisation en thérapeutique est récente et fait suite à l'identification des mécanismes moléculaires spécifiques de processus pathologiques [29][30][31]. Apparaît en filigrane le souhait d'éviter de léser les tissus sains ou encore, en restant dans la métaphore guerrière, d'éviter les dégâts collatéraux des médicaments.…”

Therapy for human gastrointestinal microsporidiosis.

“…Polyamines play an important role in the proliferation and differentiation of pathogenic protozoa. 43 These quaternary ammonium compounds (putrescine, spermidine, and spermine) are important in nucleic acid and protein synthesis. The ornithine decarboxylase (ODC) inhibitor D-Lalpha difluoromethyl ornithine (DFMO) has been effective in the treatment of African sleeping sickness.…”