Discovery of tREP-18, a novel class of tRNA encoded peptide with potent leishmanicidal activity

Abstract

In the post genomic era, tRNA-derived fragments have emerged as a new class of non-coding gene regulators, those play crucial roles both at the transcriptional and translational levels, in different cellular biogenesis. However, none of the studies has ever asked whether tRNAs can also be translated into peptides with any biological significance. Thus, we present a novel hypothesis which suggested that; design and synthesis of tRNA-derived peptides from prokaryotic genome can be exploited for developing unique chemotherapeutics against neglected tropical diseases, like Visceral leishmaniasis (VL) and its aggressive form known as post kalazar dermal leishmaniasis (PKDL). To achieve this aim, we have used a novel system biology-based strategy, which involved; i) mining of unique tRNAs from E. coli genome and their translation into peptide in silico, ii) designing of theoretical 3D models to evaluate their stability, iii) prediction of their biological activity by screening against anti-parasitic database to filter the lead peptide. Based on this strategy, a unique tRNA-derived peptide (tREP-18) was selected, chemically synthesized, and used in vitro for elucidating its therapeutic significance against L. donovani, a causative agent of VL and PKDL. Our findings demonstrated that, tREP-18 can impose high level toxicity to L. donovani promastigotes, by disrupting the ultrastructural cellular architect, destabilizing the mitochondrial membrane potential ({Delta}{Psi}m), thus leading to drastic reduction in cell viability and proliferation. It also imparted high level of toxicity to BS12 a clinical isolate of PKDL. Conceivably, we for the first time reports a novel tRNA-derived peptide "tREP18" with excellent anti-leishmanial property, which can be further utilized for developing it as antileishmanial drug. One Sentence SummaryHere we report a novel first-in-class tRNA encoded peptide and its super anti-leishmanial characteristics.