Rational design of GRK2 inhibitors for the treatment of heart failure / 中国药理学与毒理学杂志

G protein-coupled receptors (GPCRs) convert extracellular stimuli in the form of hormones, odorants and light into profound changes in cell homeostasis. Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling. Seven GPCR kinases (GRKs) phosphorylate and regulate the activity of most of the ~800 GPCRs in the human genome. Although GRKs normally play an adaptive role, in conditions such as chronic heart failure they are overexpressed and linked to disease progression. GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy, respectively. Our lab has determined atomic structures representing all three vertebrate GRK subfamilies, and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design. We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor, determined the crystal structure of the GRK2·paroxetine complex and, in collaboration with the Koch lab, showed that the drug improves contractility in myocytes and, most impressively, recovery in post-myocardial infarcted mice. Since then, we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5. Using a ″hybrid″ inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models. Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds, allowing for the design of future generations of GRK chemical probes.

[Echotomography in the diagnosis of pancreatic diseases]

The diagnostic value of pancreatic echotomography was evaluated through a series of595 pancreatic echo-tomography. The study was performed by means of a normal scanning instrument yielding delayed type images, without grey color scale. Results were classified as technical failures, [generally due to intestinal gas-interposition], accurate diagnosis, dubious, wrong diagnosis, and false positive or false negative results. 7,6% false positive results were registered among 368 patients devoid of pancreatic diseases. Among 227 patients with documented diseases the diagnosis was accurate in 62,5% of cases. This percentage rose to 71,7V% when technical failure were excluded [142 cases from 198], the best score was obtained with pancreatic pseudocysts. A comparison could be drawn between the diagnostic value of both ECT and arteriography in sixty five cases. There was no significant difference between the two methods. On the other hand retrograde wirsungography and ECT appeared to be complementary technics. When associated, these methods allowed the diagnostic accuracy to be 87% of cases. This rate was significantly higher than hese obtained by either ECT or retrograde wirsungography when utilised alone