01900nas a2200193   4500008004100000022001400041245011600055210006900171260000800240300001300248490000700261520120700268100001901475700002001494700002301514700001601537700002801553856012501581       2018                        eng d  a1545-788500aHighly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii0 aHighly diverged novel subunit composition of apicomplexan Ftype   cJUL  ae20061280 v163 a<p>The mitochondrial F-type ATP synthase, a multisubunit nanomotor, is critical for maintaining cellular ATP levels. In T. gondii and other apicomplexan parasites, many subunit components necessary for proper assembly and functioning of this enzyme appear to be missing. Here, we report the identification of 20 novel subunits of T. gondii F-type ATP synthase from mass spectrometry analysis of partially purified monomeric (approximately 600 kDa) and dimeric (&gt; 1 MDa) forms of the enzyme. Despite extreme sequence diversification, key F-O subunits a, b, and d can be identified from conserved structural features. Orthologs for these proteins are restricted to apicomplexan, chromerid, and dinoflagellate species. Interestingly, their absence in ciliates indicates a major diversion, with respect to subunit composition of this enzyme, within the alveolate clade. Discovery of these highly diversified novel components of the apicomplexan F-type ATP synthase complex could facilitate the development of novel antiparasitic agents. Structural and functional characterization of this unusual enzyme complex will advance our fundamental understanding of energy metabolism in apicomplexan species.</p>1 aSalunke, Rahul1 aMourier, Tobias1 aBanerjee, Manidipa1 aPain, Arnab1 aShanmugam, Dhanasekaran  uhttps://library.ncl.res.in/content/highly-diverged-novel-subunit-composition-apicomplexan-f-type-atp-synthase-identified01960nas a2200301   4500008004100000022001400041245004800055210004700103260000900150490000700159520111600166653001601282653001601298653002201314653001201336653001501348653001501363653000601378100002401384700002401408700001701432700002601449700002601475700001801501700002801519700002801547856008301575       2023                        eng d  a1860-717900aHistidinal-based potent antimalarial agents0 aHistidinalbased potent antimalarial agents  cMAY 0 v183 a<p>
	Herein we report the synthesis and evaluation of peptide-histidinal conjugated drug scaffolds, which have the potential to target the hemoglobin-degrading proteases falcipain-2/3 from the human malaria parasite. Scaffolds with various substitutions were tested for antimalarial activity, and compounds 8 g, 8 h, and 15 exhibited EC50 values of similar to 0.018 mu M, similar to 0.069 mu M, and similar to 0.02 mu M, respectively. Structure-based docking studies on falcipain-2/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds 8 g, 8 h, and 15 interact strongly with binding sites of falcipain-2/3 in a substrate-like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug-likeness parameters. Further, phenotypic assays revealed that compound 8 g and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain-2/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.</p>
10aartemisinin10achloroquine10adigestive vacuole10adocking10afalcipains10afalciparum10aP1 aMeena, Chhuttan, L.1 aHingamire, Tejashri1 aGupta, Tanya1 aDeshmukh, Bhagyashree1 aKarmodiya, Krishanpal1 aJoshi, Rakesh1 aShanmugam, Dhanasekaran1 aSanjayan, Gangadhar, J.  uhttps://library.ncl.res.in/content/histidinal-based-potent-antimalarial-agents