Executive Summary : | Objective: Carryout mechanistic and target identification studies for the potent antimalarial compounds NDS101348 and NDS101351. Carryout mechanistic and target identification studies for the antimalarial compounds targeting the parasite apicoplast. Testing the transmission-blocking efficacy of the antimalarial compounds. Target-based synthesis of new chemical compounds against malaria. Evaluation of compounds as anti-plasmodial agents in in vitro phenotypic screens and mouse infection model. SAR around active chemical scaffolds for optimization. Evaluation of in vitro and in vivo efficacy of selected compounds using animal models of malaria, VL and LF. 1) To functionally characterize the role of key components of energy metabolism (LdREL1, ARPs, Sterol 14 alpha demethylase) and chaperons (TCP1 subunits and HSP40) by generating gene knockout/knockdown mutants in context of the mitochondrial metabolism and parasite survival.Morphological characterization of the above mutant parasites and ultra-structural analysis of their sub-cellular organelles. Structure determination of Rab5b (nutrient uptake), y GCS and TR-inhibitor complex (hallmark of oxidative stress) of Leishmania parasite by NMR and X¬Ray. Identification and design of novel scaffolds against selected targets by in silica and chemical biology approaches, and their anti-leishmanial efficacy determination.Biochemical, biophysical and functional characterization of wBmRecA and its validation as a drug target by in silica and chemical biology approaches. |
