Protein Translation Enzyme lysyl-tRNA Synthetase Presents a New Target for Drug Development against Causative Agents of Loiasis and Schistosomiasis.
Helminth parasites are an assemblage of two major phyla of nematodes (also known as roundworms) and platyhelminths (also called flatworms). These parasites are a major human health burden, and infections caused by helminths are considered under neglected tropical diseases (NTDs). These infections are typified by limited clinical treatment options and threat of drug resistance. Aminoacyl-tRNA synthetases (aaRSs) are vital enzymes that decode genetic information and enable protein translation. The specific inhibition of pathogen aaRSs bores well for development of next generation anti-parasitics. Here, we have identified and annotated aaRSs and accessory proteins from Loa loa (nematode) and Schistosoma mansoni (flatworm) to provide a glimpse of these protein translation enzymes within these parasites. Using purified parasitic lysyl-tRNA synthetases (KRSs), we developed series of assays that address KRS enzymatic activity, oligomeric states, crystal structure and inhibition profiles. We show that L. loa and S. mansoni KRSs are potently inhibited by the fungal metabolite cladosporin. Our co-crystal structure of Loa loa KRS-cladosporin complex reveals key interacting residues and provides a platform for structure-based drug development. This work hence provides a new direction for both novel target discovery and inhibitor development against eukaryotic pathogens that include L. loa and S. mansoni.
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
Arvind
A
Sharma
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
Manmohan
M
Sharma
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
Manickam
M
Yogavel
Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
Amit
A
Sharma
D000595:Amino Acid Sequence; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008117:Loa / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D008118:Loiasis / Q000188:drug therapy / Q000469:parasitology*; D008250:Lysine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012550:Schistosoma mansoni / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D012552:Schistosomiasis / Q000188:drug therapy / Q000469:parasitology*; D016415:Sequence Alignment
D000871:Anthelmintics; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D008250:Lysine-tRNA Ligase