Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part I: Drug resistance

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

Section: Atp-binding Cassette (Abc)mentioning

confidence: 98%

Section: Water and Ion Channelsmentioning

confidence: 99%

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

Abaza

2022

“…Such metabolic phenotyping was successfully used to study various biologic processes (drug susceptibility or resistance) and disease states (subclinical, acute and chronic) [4] . Genome wide-single nucleotide polymorphism (SNP) analyses that involves germline substitution of a single nucleotide in the parasite genome to pinpoint gene mutation linked to drug resistance, was recently reviewed [28] .…”

Section: Approachesmentioning

confidence: 99%

“…The worldwide antimalarial resistance network (wwarn.org), a global network of academic experts, was established aiming to identify and track the global spread of malaria drug resistance. As previously reviewed [28] , anti-malarial drugs resistance are associated with established definitive genetic markers. In vitro evolution and whole-genomic analysis is nowadays a new approach to identify the molecular mechanisms of anti-malarial drugs resistance, i.e., Plasmodium resistome [54] .…”

Section: Drug Resistancementioning

confidence: 99%

Omics: Approaches and applications related to diagnosis, treatment, and control of parasitic diseases. Part I: Plasmodium spp.

Diab

Younis

2022

Over the last two decades, omics studies provide a revolutionary advance of datasets in the field of Medical Parasitology for understanding parasite system biology, host-parasite interactions, and phylogenetic analyses; i.e., genomics, transcriptomes, proteomics, metabolomics. Together with bioinformatics, genome-wide associated studies (GWASs) enabled scientists to identify diagnostic biomarkers, promising drug targets, and potential vaccine candidates for diagnosis, treatment, and protection against several neglected tropical diseases. Omics approaches are either structural (genomics) or functional (post-genomics). To survive, Plasmodium spp. are able to delete certain genes unessential for their survival and growth, enabling them to evade host immune response. In addition, they undergo antigenic variations that lead to gene mutations in enzymes controlling drug uptake. Previously unattainable goals, e.g., host immunoevasion, susceptibility or resistance to infection, drug resistance, novel drugs as well as prevention and control were achieved by omics studies powered by bioinformatics tools. This part of the present review aims to shed light on omics application outcomes regarding Plasmodium spp.

“…Since all currently available therapeutic drugs are only effective against tachyzoites with poor efficacy against tissue cysts, there is much controversy in treatment of chronic toxoplasmosis. As previously reviewed [6] , drug resistance developed against several anti-Toxoplasma drugs due to gene mutations. Recent evolutionary technology enabled investigators to understand T. gondii biology system and uncover new drug targets.…”

Section: Introductionmentioning

confidence: 99%

The therapeutic efficacy of curcumin nanoemulsion versus Spiramycin in Toxoplasma gondii (ME49 strain) chronically infected mice

Rageh¹,

Abaza²,

El-Gayar³

et al. 2022

Background: Previously, we showed that curcumin (CUR) nanoemulsion exhibited a promising prophylactic effect on acute toxoplasmosis, and decreased parasite burden. Scanning electron microscopy (SEM) of the peritoneal exudates showed deformed tachyzoites in both prophylactic and treated subgroups. Objective: The present study is designed to evaluate the therapeutic effect of CUR nanoemulsion compared to that of Spiramycin on T. gondii type II, ME49 strain causing chronic toxoplasmosis in experimentally infected mice. Material and Methods: This case-control experimental study included 30 Swiss albino mice, divided into three equal groups. All mice were infected with avirulent ME49 strain to induce chronic toxoplasmosis. The study included group I (infected non-treated), II (infected treated with CUR nanoemulsion), and III (infected and treated with Spiramycin). The assessment parameters included estimation of the mortality rate, and parasite burden (cyst number and size) in livers and spleens impression smears, and in brains homogenates. Results:The mortality rate was 40% in the infected non-treated group with no mortality in all treated mice. There was a significant decrease of cyst number and size in livers, spleens, and brains of both treated groups as compared to the infected non-treated mice. Conclusion: It was concluded that CUR nanoemulsion had a promising therapeutic effect on chronic toxoplasmosis.