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Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation

Authors
Journal
BMC Pharmacology
1471-2210
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Volume
9
Identifiers
DOI: 10.1186/1471-2210-9-s1-p26
Keywords
  • Poster Presentation
Disciplines
  • Biology

Abstract

1471-2210-9-S1-P26.fm ral ss BioMed CentBMC Pharmacology Open AccePoster presentation Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation Linda Sarah Hoffmann*1,2, Peter Michael Schmidt3, Yvonne Keim1, Stefan Schaefer1, Harald Schmidt4 and Johannes-Peter Stasch1,2 Address: 1Pharma Research Centre, Bayer HealthCare, Aprather Weg 18a, Wuppertal, Germany, 2Martin-Luther-University, School of Pharmacy, Halle, Germany, 3CSIRO Molecular Health Technologies, 343 Royal Parade, Parkville, Vic., Australia and 4Department of Pharmacology & Centre for Vascular Health, Monash University, Melbourne, Clayton, Vic., Australia Email: Linda Sarah Hoffmann* - [email protected] * Corresponding author Background In endothelial dysfunction, signalling by nitric oxide (NO) is impaired because of the oxidation and subse- quent loss of the soluble guanylyl cyclase (sGC) haem [1]. The sGC activator 4-[((4-carboxybutyl){2-[(4-phenethyl- benzyl)oxy]phenethyl}amino)methyl [benzoic]acid (BAY 58-2667) is a haem-mimetic able to bind with high affinity to GC when the native haem (the NO binding site) is removed and it also protects sGC from ubiquitin- triggered degradation [2-4]. Here we investigate whether this protection is a unique feature of BAY 58-2667 or a general characteristic of haem-site ligands such as the haem-independent sGC activator 5-chloro-2-(5-chloro- thiophene-2-sulphonylamino-N-(4-(morpholine-4- sulphonyl)-phenyl)-benzamide sodium salt (HMR 1766), the haem-mimetic Zn-protoporphyrin IX (Zn- PPIX) or the haem-dependent sGC stimulator 5-cyclopro- pyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-pyrimidin-4-ylamine (BAY 41-2272). Experimental approach The sGC inhibitor 1H-(1,2,4)-oxadiazolo[4,3-a]quinoxa- lin-1-one (ODQ) was used to induce oxidation-induced degradation of sGC. Activity and protein levels of sGC were measured in a Chinese hamster ovary cell line as well mu

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