Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Abstract

The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such African sleeping sickness, Chagas' disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets.

Metabolomics analysis of a mouse model for chronic exposure to ambient PM2.5

“…Furthermore, CAP exposure significantly decreased the levels of circulating 1,5anhydroglucitol and tagatose, both of which are inversely correlated with risk for type 2 diabetes mellitus (Ensor et al, 2014;Hashimoto and Koga, 2015). Additionally, chronic exposure to CAP significantly decreased erythrose 4-phosphate, which is an intermediate in Calvin cycle and the pentose phosphate pathway (Loureiro et al, 2017).…”

Murine infection with bioluminescent Leishmania infantum axenic amastigotes applied to drug discovery

“…As there is still no vaccine available for humans, disease control relies mostly on chemotherapy and vector control. Therefore, the limited and unsatisfactory chemotherapeutic options dictate the need for new drugs 3,4 . Indeed, every year up to 30,000 individuals suffering from VL die, some of them due to clinical treatment failure (associated with drug resistance, drug quality/misuse and infection status) 1,5 .…”

Toward Chemical Validation of Leishmania infantum Ribose 5-Phosphate Isomerase as a Drug Target

“…Compounds were assayed against both L. infantum promastigotes (wild-type and LiRpiB sKO) and intra-on May 4, 2021 by guest http://aac.asm.org/ Downloaded from macrophagic amastigotes (Table 2). As 4-PEH is only an inhibitor of LiRpiB at high millimolar range in protein activity assays (10 mM was routinely used to achieve inhibition during this study), it had been anticipated to show little to no anti-parasitic activity in vitro/in vivo (7), which was shown to be the case in treating with 100 µM.…”

“…The enzyme ribose-5-phosphate isomerase (Rpi) catalyses the isomerization of ribose-5-phosphate (R5P) to ribulose-5-phosphate (Ru5P) (Figure S1) in the non-on May 4, 2021 by guest http://aac.asm.org/ Downloaded from oxidative branch of the pentose phosphate pathway (PPP) (Figure 1) (6,7).…”