Biology subjects

Ranganathan, A.

Publications and source records attributed to Ranganathan, A..

2 recordsLinked to original sources

bioRxiv2021

Targeting the artemisinin resistant malaria by repositioning of the anti-Hepatitis C Virus drug Alisporivir

The rapid emergence of P. falciparum-resistant strains raises an urgent need to find new antimalarial drug candidates. This study reports the rational repositioning of the anti-Hepatitis C Virus drug, Alisporivir, a non-immunosuppressive analog of cyclosporin A (CsA) against multiple, drug-resistant strains of P. falciparum. Alisporivir being non-hemolytic has been proven to be a better drug than CsA. Indeed, our study also demonstrated the same. Alisporivir inhibited chloroquine-sensitive parasite growth with an IC50 of 196.6nM. Alisporivir also inhibited the growth of chloroquine-resistant parasites with an IC50 of 422.1nM. Alisporivir exhibited, anti-malarial activity in in vivo. Further, we exploited the Cyclophilins targeting potential of Alisporivir against artemisinin-resistant malaria parasite owing to the fact that PfCyP-19B is one of the genes that is overexpressed in artemisinin-resistant parasite revealed by a population transcriptomic study. Our semiquantitative real-time transcript and immunofluorescence analysis confirmed the overexpression of PfCyP-19B in Artemisinin-resistant P. falciparum (PfKelch13R539T). Artemisinin resistance is attributed to slow clearance of ring stage parasites. Ring survival assay (RSA) is designed to access the potency of compounds on these dormant slow clearing parasites leading to drug resistance. Thus, the potency of Alisporivir against PfKelch13R539T was evaluated by RSA. A 2.5-fold decrease in parasite survival was detected with Alisporivir. Further, combination of Alisporivir with DHA found to potentiate the efficacy of DHA by 4.55-fold. These results support the hypothesis that targeting of resistance mechanism is a potential approach to deal with resistant parasite. Overall, this study demonstrates the rational reposition of Alisporivir against resistant malaria resistance.

microbiology↗

bioRxiv2020

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

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.

synthetic biology↗