Ether–lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether–lipid analogues in Leishmania

Leishmania donovani Resistance to Miltefosine Involves a Defective Inward Translocation of the Drug

“…However, little is known about the leishmanicidal and trypanocidal mechanisms of HePC and other alkyl-lysophospholipids. Perturbation of the alkyl-lipid metabolism and the biosynthesis of alkyl-anchored glycoproteins (15), as well as damage to the flagellar membrane and phospholipid biosynthesis (14,25), have been described. The mechanisms of action of this class of drugs against tumor cell lines have been linked to (i) nonspecific ion channel formation, (ii) cell signaling inhibition through phospholipase C inactivation, and (iii) inhibition of de novo phosphatidylcholine (PC) and sphingomyelin synthesis, leading to the accumulation of ceramides and apoptosis (33).…”

The Role of Genome Sequencing in the Identification of Novel Therapeutic Targets

“…Open reading frame prediction algorithms, such as GRAIL or GENSCAN [49][50][51][52][53][54][55] are ~70% accurate in predicting exons from eukaryotic genomic sequences [56]. These algorithms, however, have more difficulty in determining which exons constitute one single open reading frame versus identifying one short single exon [57][58][59][60][61]. Updated lists of genome sequencing projects and sequence data are available at the Multipurpose Automated Genome Project Investigation Environment, National Center for Biotechnology Information and the Institute for Genomic Research World Wide Web sites.…”

Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs

“…Due to its molecular structure, LPAs have been intensively investigates as potential inhibitors of the enzymes involved in the synthesis, degradation and modification of the lipid membrane (Wieder et al 1999). The metabolism of miltefosine was investigated in L. mexicana (Lux et al 2000) and it was found that these compounds inhibit the specific alkyl-specific acyl CoA acyltransferase, a key enzyme for ether lipid remodeling, which may exert an effect on cellular growth of parasites. PCD in Leishmania due to miltefosine is characterized by a typical apoptotic phenomenon, such as cellular shrinking, DNA fragmentation and phosphatidyl serine exposition, with preservation of the integrity of the plasmatic membrane, which may cause programmed cell death in these organisms and can explain the selective antiparasitic effects of such compounds in vivo (Paris et al 2004).…”