Genetic manipulation of Leishmania donovani threonyl tRNA synthetase facilitates its exploration as a potential therapeutic target.
Sanya ChadhaRamachandran VijayanSakshi GuptaManoj MundeSamudrala GourinathRentala MadhubalaPublished in: PLoS neglected tropical diseases (2018)
Recombinant LdThrRS displayed aminoacylation activity, and the protein is possibly localized to both the cytosol and mitochondria. The comparison of the 3D-model of LdThrRS to human ThrRS displayed considerable similarity. Heterozygous parasites showed restrictive growth phenotype and had attenuated infectivity. These heterozygous parasites were more susceptible to inhibition by borrelidin. Several attempts to obtain ThrRS homozygous null mutants were not successful, indicating its essentiality for the Leishmania parasite. Borrelidin showed a strong affinity for LdThrRS (KD: 0.04 μM) and was effective in inhibiting the aminoacylation activity of the rLdThrRS (IC50: 0.06 μM). Borrelidin inhibited the promastigotes (IC50: 21 μM) stage of parasites. Our data shows that LdThrRS is essential for L. donovani survival and is likely to bind with small drug-like molecules with strong affinity, thus making it a potential target for drug discovery efforts.
Keyphrases
- plasmodium falciparum
- drug discovery
- early onset
- endothelial cells
- cell death
- human health
- electronic health record
- genome wide
- big data
- emergency department
- gene expression
- quality improvement
- risk assessment
- small molecule
- capillary electrophoresis
- pluripotent stem cells
- toxoplasma gondii
- machine learning
- data analysis
- wild type
- artificial intelligence