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1. WO2000028076 - REGULATION OF NITRIC OXIDE SYNTHASE ACTIVITY

Publication Number WO/2000/028076
Publication Date 18.05.2000
International Application No. PCT/AU1999/000968
International Filing Date 05.11.1999
Chapter 2 Demand Filed 18.05.2000
IPC
C12Q 1/26 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
26involving oxidoreductase
CPC
C12Q 1/26
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms
26involving oxidoreductase
Applicants
  • ST. VINCENT'S INSTITUTE OF MEDICAL RESEARCH [AU]/[AU] (AllExceptUS)
  • STAPLETON, David, Ian [AU]/[AU] (UsOnly)
  • CHEN, Zhiping [AU]/[AU] (UsOnly)
  • MICHELL, Belinda, Joyce [AU]/[AU] (UsOnly)
  • KEMP, Bruce, Ernest [AU]/[AU] (UsOnly)
  • MITCHELHILL, Kenneth, Ian [AU]/[AU] (UsOnly)
Inventors
  • STAPLETON, David, Ian
  • CHEN, Zhiping
  • MICHELL, Belinda, Joyce
  • KEMP, Bruce, Ernest
  • MITCHELHILL, Kenneth, Ian
Agents
  • GRIFFITH HACK
Priority Data
PP 697606.11.1998AU
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) REGULATION OF NITRIC OXIDE SYNTHASE ACTIVITY
(FR) REGULATION DE L'ACTIVITE DE LA MONOXYDE D'AZOTE-SYNTHASE
Abstract
(EN)
This invention relates to the regulation of the activity of the enzyme nitric oxide synthase, and in particular to regulation of activity of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS and nNOS$g(m)). According to a first aspect, the invention provides a method of identifying modulators of AMPK-mediated activation of eNOS, comprising the step of testing putative modulators for their ability to increase or decrease phosphorylation of eNOS depending on the calmodulin and calcium ion concentrations. In an alternative aspect, the invention provides a method of identifying modulators of AMPK-mediated inhibition of eNOS, comprising the step of testing a putative modulator for its ability to decrease or increase AMPK-mediated phosphorylation of eNOS in the presence of limiting calcium ions. Preferably specific phosphorylation of threonine 495 is assessed. According to a second aspect, the invention provides a method of identifying modulators that either promote or inhibit phosphorylation of nNOS and nNOS$g(m) at Ser-1417. Compounds which activate the AMP-activated protein kinase are expected to be useful in the treatment of ischaemic heart disease by promoting both glucose and fatty acid metabolism, as well as by increasing NOS activity to improve nutrient and oxygen supply to the myocytes and to reduce mechanical activity. These compounds would also have utility in the treatment of pulmonary hypertension and in obstructive airways disease.
(FR)
L'invention concerne la régulation de l'activité de l'enzyme monoxyde d'azote-synthase et notamment la régulation de l'activité de la monoxyde d'azote-synthase endothéliale (eNOS) et de la monoxyde d'azote-synthase neuronale (nNOS et nNOS$g(m)). Dans un premier aspect, l'invention concerne un procédé d'identification des modulateurs de l'activation d'eNOS à médiation par AMPK, y compris le stade de vérification des modulateurs putatifs visant à déterminer leur capacité d'augmenter ou de diminuer la phosphorylation d'eNOS à médiation par AMPK en présence d'ions de calcium de limitation. De préférence, on fait une estimation de la phosphorylation spécifique de thréonine 495. Dans un deuxième aspect, l'invention concerne un procédé pour identifier des modulateurs qui favorisent ou inhibent la phosphorylation de nNOS et de nNOS$g(m) dans Ser-1417. On attend des composés qui activent la protéine kinase activée par AMP qu'ils soient utiles dans le traitement de la cardiopathie ischémique en favorisant le métabolisme du glucose et des acides gras et en augmentant en même temps l'activité de NOS de manière à améliorer l'alimentation des myocytes en oxygène et en substances nutritives et à réduire l'activité mécanique. Ces composés pourraient également servir dans le traitement de l'hypertension pulmonaire et de la maladie obstructive des voies respiratoires.
Also published as
US09807877
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