Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part II: Parasite targets

Abstract

Growth and replication (DNA synthesis and gene expression) 1. Nucleic acids synthesisNucleotides serve as monomeric units of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). They are formed of a nitrogenous base (nucleoside), five-carbon sugars (ribose or deoxyribose), and a phosphate group (1-3 phosphates). Accordingly, they are termed monophosphate (MP), diphosphate (DP), and triphosphate (TP), respectively. Symthesis of DNA and RNA copies requires supply of two nitrogenous bases (purines and pyrimidines) in similar quantities. As long as both bases are available, synthesis is self-activated, and when there are no more bases, the synthesis is self-inhibited. While purines include adenine (A), and guanine (G), pyrimidines include cytosine (C), thymine (T), and uracil (U). Notably, DNA is formed of two purines (A and G), and two pyrimidines (C and T), while (U) replaces (T) in RNA. Nucleotides have several cellular functions including growth and replication via synthesis of DNA and RNA signaling pathways since they are involved in synthesis of intracellular cyclic second messengers (cAMP, and cGMP). They are energy sources due to involvement of nitrogenous bases in the components of nucleoside TPs (ATP, GTP, TTP, CTP, and UTD). Energy is required for protein and cell membrane syntheses, cell division, and motility. Moreover, adenine contributes in formation of several cofactors required for enzymatic reactions such as coenzyme A, nicotinamide adenine dinucleotide (NAD), NAD phosphate (NADP), flavine adenine dinucleotide (FAD) and flavine mononucleotide (FMN). Lastly, uracil diphosphate (UDP) is utilized in glucogenesis; a ubiquitous metabolic pathway required for production of glucose from non-carbohydrate carbon substrates [2] .Synthesis of purine and pyrimidine nucleotides is either de novo or through a salvage pathway. In such a pathway, nucleoside transporters (NTs), known also as permeases, carry salvaged bases and nucleosides across parasite plasma membrane to synthesize nucleotides. Therefore, nucleoside transporters and enzymes involved in purine or pyrimidine synthesis, either de novo or via salvage pathways contributing to nucleic acid processing, are potential drug targets.Transporters: There are four balanced NTs (ENTs). While ENT1 and ENT2 are the major

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

“…PMM is additionally combined with stearyl amine (SA)-containing phosphatidylcholine (PC) liposomes. PMM-SA-PM revealed enhanced immune protection, antileishmanial activity, and no toxicity …”

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

“…As previously reviewed [31] , adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and HGXPRT are essential enzymes in purine salvage pathway. Besides, inosine monophosphate dehydrogenase (IMPDH) obtained from Staphylococcus aureus, an enzyme producing NADH over time to monitor the activity of purine pathway, gained much attention for treatment of multi-drug resistant bacterial and fungal infections, i.e., a valuable drug target.…”

“…Later, virtual screening of 51 inhibitors revealed that MC1742-12 displayed in vitro satisfactory results against P. falciparum, but it failed to reduce parasitemia in P. berghei-infected mice [60] . (iii) BDPs: As previously explained [31] , BDPs are conserved acetyl-lysine-specific protein-interaction modules that play important roles in regulating gene expression and mutations. In other words, they are proteins with a domain known to recognize acetyl-lysine residues on histones.…”

“…As previously explained [31] , the genetic code is a set of three letters (AUG) of nucleotides; adenosine (A), uracil (U) and guanosine (G) called codons. The rate of translational protein synthesis machinery is maintained by upstream AUGs (uAUGs).…”