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

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Most of the cysteine proteases (CPs) expressed by ectoparasites belong to the papain-like superfamily (clan CA, family C1) and are associated with the physiological events during different developmental life stages. Cathepsins, legumains/asparaginyl endopeptidases and caspases (clan CA, family C1, C13 and C14, respectively) play a major role in mosquito biology. There is accumulating evidence that CPs expressed by arthropods may play a role in clinical presentations of some transmitted parasitic disease, e.g. babesiosis. During blood meals, salivary glands secrete bioactive substances, including CPs, to exert several pharmacological properties that assist ectoparasites to evade host defense responses and to induce inflammatory reactions. Furthermore, they play an important role in extracellular and intracellular proteins degradation as well as their processing. In this regard, cystatins (CYSs) were found to inhibit insect CPs suggesting its use as targets for control of mites and ticks. The present review aims to identify different CPs expressed in ectoparasites, the main vectors of several endemic diseases such as malaria, babesiosis, Chagas' and Lyme disease. Meanwhile, it highlights different CYSs that could be used as biological insecticides to control diseases transmitted by mites and ticks.

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In the last two decades, transporters attracted much attention in identification of potential drug targets against intracellular protozoa. Several membrane molecules exhibit essential roles in trafficking pathways for nutrients, essential enzymes and virulence factors. In this context, P. falciparum possesses a complex of genomic plasticity-encoding transporters with high potentiality for aneuploidy, and gene expression modulation in response to drug exposure. Therefore, it is able to undergo gene mutations in enzymes controlling drug uptake, and evade host immune response by antigenic variations as well. The genetic mechanism of antimalarial drug resistance arises early with monotherapy using fast-acting drugs or a single targeting drug. Accordingly, combined therapy acting on multiple targets would decrease the emergence of drug resistance. Evolutionary technology on genetic approach enabled researchers to identify and propose novel Plasmodium drug targets. The main objective of this part is to review potential drug targets for apicomplexans and discuss recent approaches in identifying Plasmodium targets, as well as advances in the design and development of novel antimalarial drugs.

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New drug targets-XI Malignant malaria: Active site inhibitors are confronted by high drug pressure, and more susceptibility to parasite gene mutations commonly linked with resistance of anti-malarial drugs. On the other hand, allosteric inhibition (previously described; New drug targets IX, PUJ 2019; 12(1):68-71) is an alternative strategy to design an efficient inhibitor. Briefly, allosteric control means function regulation of a protein by binding an effector molecule at a site other than its active site. Allosteric site allows the effector molecules to activate or inhibit protein functional dynamics. Therefore, allosteric inhibitors are not associated with parasite gene mutation because they don't alter the active site. A group of scientists (Arnold Amusengeri et al.) from South Africa and USA succeeded to identify allosteric modulators (SANC190 and SANC651) against P. falciparum HSP70-1 and HSP70-x. Transcriptomic analysis of P. falciparum revealed six essential HSP70 isoforms; x-z and 1-3. The investigators selected HSP70-1 and HSP70-x because both are maximally expressed during the asexual erythrocytic stages of P. falciparum. Besides, PfHSP70-1 was reported as survival factor, while PfHSP70-x was essential as an efficient exporter of a key virulence factor; erythrocyte membrane protein-1. Studies that utilized atom molecular dynamic simulations to identify allosteric dynamic hotspots for human HSPs 70 and 90 encouraged the investigators to develop promising modulators for PfHSP70-1 and PfHSP70-x.