Drug Development using Eukaryotic Parasites' Aminoacyl-tRNA Synthetases

Abstract

There is significant human morbidity and mortality due to parasitic diseases. Many parasitic infections are difficult to control and eradicate because new drug-resistant parasite strains are constantly developing and spreading. Aminoacyl-tRNA synthetases (aaRSs) are common enzymes necessary for the production of proteins. This enzyme family has been proven to be druggable through the invention and production of numerous small molecule, drug-like inhibitors against parasite-encoded and expressed aaRSs. In this work, we summarise the progress made so far in determining the druggability of aaRSs in terms of their biochemical characterization, validation as targets, inhibitor development, and structural interpretation from parasites that cause trypanosomiasis, toxoplasmosis, leishmaniasis, lymphatic filariasis, toxoplasmosis, toxoplasmosis, and toxoplasma gondii (Trypanosoma). Thus, our work offers a solid framework for the methodical separation of aaRSs from various infections and will make it easier to combine possible inhibitors to hasten the development of antiparasitic drugs.

Introduction

More than a million infections are present and continue to spread throughout the world as a result of various eukaryotic parasites, placing a strain on public health initiatives and the economy. The periodic and unavoidable emergence of medication resistance in parasites and pesticide resistance in vectors make the development of innovative pharmaceuticals necessary for the effective treatment and control of parasitic illnesses. There is a pressing need for innovative antiparasitic drug scaffolds since such obstacles to successful treatment could allow parasitic illnesses to reemerge. 

Eukaryotic parasites can infect hosts such as humans and animals and spread a variety of diseases of varied severity. Malaria, toxoplasmosis, and cryptosporidiosis are all caused by the parasites Plasmodium, Toxoplasma gondii, and Cryptosporidium, all members of the phylum Apicomplexa. After the growth and death of red blood cells, Plasmodium species cause the most severe types of infection in humans, with an estimated 241 million cases of malaria in 85 endemic countries. 

According to estimates, 25–30% of the world's population is chronically infected with this parasite. Sporozoites are released following cyst ingestion by the human hosts. These sporozoites invade intestinal epithelial cells, where they transform into tachyzoites that replicate and infect more cells. The disease's severe symptoms are accounted for by these stages collectively, and there are few medications available to treat toxoplasmosis.

Targets for antiparasitic medications include aminoacyl-tRNA synthetase (aaRSs).

Since they catalyse the joining of cognate amino acids that correspond to the tRNA anticodon triplet, the aminoacyl-tRNA synthetase (aaRSs) family of enzymes, also known as aminoacyl-tRNA ligases, are found in all living things (2, 10, 11, 12, 13). (Fig. 2). First, aaRS uses an ATP molecule to activate the corresponding amino acid, creating an active aminoacyl-adenylate intermediate (amino acid-AMP), which releases pyrophosphate (PPi). The enzyme binds to the cognate tRNA, which then transfers the amino acid to the 3' end of the tRNA and releases AMP. 

Elongation factors then deliver the aminoacylated tRNA to the ribosome for protein synthesis after it has served as a crucial substrate for protein translation. Additionally, editing domains found in aminoacyl-tRNA synthetases guarantee excellent fidelity of tRNA charging. By hydrolyzing incorrectly activated amino acids (pre-transfer to the tRNA) and incorrectly acylated tRNAs using various post-transfer editing domains, the aaRSs decrease mistakes. Thus, aminoacyl-tRNA synthetases are crucial enzymes for protein synthesis because they ensure the precision of protein translation and supply aminoacylated-tRNA with the homologous amino acid. In addition to their catalytic function, the aaRSs play a role in the regulation of transcription, the production of signal molecules, and mitochondrial RNA breakage. According to their structural differences, the aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aaRSs are primarily monomeric and contain the Rossman fold catalytic domain. 

Conclusion

Protein synthesis depends on the generally conserved enzymes known as aminoacyl-tRNA synthetases (aaRSs). The parasite-encoded aaRSs have emerged as promising therapeutic targets for numerous infections as a result of the remarkable development made over the past 20 years. The inhibitory methods that target different locations on these enzymes have been clarified through biochemical and structural research. In fact, a striking instance of the double drugging of this enzyme family has also been verified, in which the prolyl-tRNA synthetase is co-bound by two distinct, individually strong medicines, occluding all of the enzyme's substrate binding sites. 

Antiparasitic medication resistance is still a serious problem that requires special attention throughout the preclinical stages of inhibitor development. Inhibitors can be put on a solid route and become promising scaffolds through early studies. Furthermore, despite the fact that some parasites are evolutionarily distinct and cause different diseases, selectivity is still a problem for creating effective medications against parasite aaRSs due to the universal nature of aaRSs enzymes. Because this causes host cytotoxicity, an inhibitor must be selective towards the parasite aaRS and not the human host aaRS. Selectivity is a significant issue that demands consideration and necessitates a complete grasp of the structural bases for particular medication design. The information gathered in this study will open the door to more in-depth analysis of aaRSs from eukaryotic pathogens and direct the development of selective drug-like molecules from promising inhibitors and scaffolds. Unquestionably intriguing and promising as druggable targets, parasite-encoded aaRSs need continuing consideration for the creation of anti-infective medications.