Research Projects

Aminoacyl-tRNA synthetases (aaRSs) play a significant role in protein translation and are essential for the interpretation of genetic code [1]. Each aaRS attaches the cognate amino acid to its cognate tRNA in a process entirely reliant. Typically, an aaRS consists of catalytic and anticodon binding domains. The first domain binds cognate amino acid with ATP molecule. It activates it into an intermediate, the so-called aminoacyl-adenylate, while the latter part interacts with the anticodon region of cognate tRNA. The human malarial parasite encodes ~5300 proteins and needs to be translated efficiently in the host using parasite molecular motors like aaRSs. The parasite contains its own translation protein set and seems to not rely on host enzymes. These facts provide an opportunity to target this vital function in the parasite to kill protozoan parasites. The bioinformatics analysis of these aaRSs from P. falciparum (Pf) revealed that Pf has the highest aaRSs fraction compared to the size of its proteome [2]. Consequently, based on their distinct functional and structural characteristics, aaRSs are attractive targets for the development of drugs that target P. falciparum/P. vivax. The antibiotic mupirocin, which specifically inactivates bacterial isoleucyl-tRNA synthetase, provides the clinical applications of an aaRS inhibitor [3]. Similar to this, the broad-spectrum antifungal 5-fluoro-1,3,dihydro-1-hydroxy-2,1-benzoxazole prevents the enzyme's editing site from being used to produce yeast cytoplasmic leucyl-tRNA synthetase [3]. More recently, scientists at GlaxoSmithKline (GSK) screened ~2 million-compound libraries and identified new aaRSs inhibitors active against blood-stage malaria, reinforcing the idea that these enzymes are promising anti-protozoan targets (Gamo et al., 2010). Along the same lines, Istvan et al. confirmed the relevance of targeting these enzymes while proposing a new approach to identify and validate chemo targets in P. falciparum [4]. Similarly, a new series of bicyclic azetidine compounds have also been reported to target Plasmodium phenylalanyl-tRNA synthetase (PheRS) with a high selectivity [5–7]. It is established that inhibitijng Pf/Pv PheRS, the parasite loses it capability for protein translational machinery, thereby depicting its importance in parasite survival. Further, a recent study by Xie et al 2022 identified the adenosine 5′-sulfamate (AMS) as broad specificity of compound binding and inhibiting Pf tyrosyl-tRNA-synthetase (PfTyrRS) plasmodium aaRSs [8]. The identified compound AMS, however, though binding and killing Pf3D7 cells also showed toxicity against mammalian cell lines [8]. Given the broad spectrum inhibition of apicomplexan growth by the inhbition of PheRS and the newly identified AMS compound targeting Pf aaRS, we propose optimization of AMS and generation of its analogs to check the binding and inhibition potential of AMS derived compounds against Pf/PvPheRS.