Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

Abstract

Malaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the Plasmodium genus. Only a few WHO-recommended treatments are available to prevent or cure plasmodial infections, but genetic mutations in the causal parasites have led to onset of resistance against all commercial antimalarial drugs. New drugs and targets are being investigated to cope with this emerging problem, including enzymes belonging to the main metabolic pathways, while nucleoside and nucleotide analogues are also a promising class of potential drugs. This review highlights the main metabolic pathways targeted for the development of potential antiplasmodial therapies based on nucleos(t)ide analogues, as well as the different series of purine-containing nucleoside and nucleotide derivatives designed to inhibit Plasmodium falciparum purine metabolism.

New Benzoxazole Derivatives as Antiprotozoal Agents: In Silico Studies, Synthesis, and Biological Evaluation

“…e crystal structure of PfPNP is available in the protein data bank (PDB) with PDB ID of 3PHC [54]. e crystal structure of PfPNP showed a homohexamer (in contrast to its human analog, which is a homotrimer [55]), and it is organized as a trimer of dimers, where in each monomer, the active site is completely occupied via the cocrystallized ligand (immucillin) and one sulfate [41]. Two analogous catalytic sites are localized between each of the dimer pairs and are correlated by a noncrystallographic two-fold axis.…”

The RNA Structurome in the Asexual Blood Stages of Malaria Pathogen Plasmodium falciparum

“…We have identified base-paired mRNA elements in the coding region of P. falciparum metabolic enzymes, with most enrichment of duplex RNAs in the Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (PF3D7_1012400) and Adenosylhomocysteinase (SAHH) (PF3D7_0520900). Since most parasitic protozoa do not have the de novo purine nucleotide biosynthesis pathway and rely mostly on the salvage pathway for purine metabolism where hypoxanthine is the key precursor, HGPRT in this pathway makes a promising drug target for P. falciparum infection (Cheviet et al 2019). However, the cellular interactions and importance of these novel mRNA structural elements in the coding regions of metabolic enzymes remain to be analyzed.…”

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

“…The modulation of the activity of carbohydrate processing enzymes represents an important therapeutic target, given the involvement of these proteins in a plethora of metabolic events causing a variety of diverse pathologies [1][2][3]. Over the last decades, intense efforts have been focused on the identification of inhibitors or enhancers of such enzymes [1,[4][5][6][7] with promising therapeutic applications for the treatment of viral infections [8,9], cancer [10], diabetes [11], tuberculosis, lysosomal storage diseases [12], and parasitic protozoa [13]. An illustrative example in this area is represented by the class of iminosugars [4,5,7,14], glycomimetics (carbohydrate analogues) having the ring oxygen replaced by an amino group.…”