136185-97-2Relevant academic research and scientific papers
Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
Gerndt, Susanne,Chen, Cheng-Chang,Chao, Yu-Kai,Yuan, Yu,Burgstaller, Sandra,Rosato, Anna Scotto,Krogsaeter, Einar,Urban, Nicole,Jacob, Katharina,Nguyen, Ong Nam Phuong,Miller, Meghan T.,Keller, Marco,Vollmar, Angelika M.,Gudermann, Thomas,Zierler, Susanna,Schredelseker, Johann,Schaefer, Michael,Biel, Martin,Malli, Roland,Wahl-Schott, Christian,Bracher, Franz,Patel, Sandip,Grimm, Christian
, (2020/05/08)
Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.
Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases
Davies, Matthew,Heikkil?, Timo,McConkey, Glenn A.,Fishwick, Colin W. G.,Parsons, Mark R.,Johnson, A. Peter
supporting information; experimental part, p. 2683 - 2693 (2010/01/16)
Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUTLeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
Synthesis and Biological Activity of a Series of Diaryl-Substituted α-Cyano-β-hydroxypropenamides, a New Class of Anthelmintic Agents
Sjogren, Eric B.,Rider, Michael A.,Nelson, Peter H.,Bingham, Stanford,Poulton, Anthony L.,et al.
, p. 3295 - 3301 (2007/10/02)
A series of α-cyano-β-hydroxypropenamides was prepared and tested for anthelmintic activity. α-Cyano-β-hydroxy-N--3-propenamide (1) showed good activity against the nematode Nematospirodes dubius in a mixed parasite infection in mice; several of the analogues were also effective against the cestode Hymenolepis nana.In sheep trials, 1 caused 100percent reduction of the hematophagous nematode Haemonchus contortus after a single dose of 20 mg/kg but did not show satisfactory control of Trichostrongylus colubriformis or Ostertagia circumcincta.Against the liver fluke Fasciola hepatica, 1 suppressed egg production but only temporarily, suggesting that the adult flukes were not eliminated.Mechanism of action studies on 1 using Ascaris mitochondria showed it to be an uncoupler of oxidative phosphorylation.
