My overall research goal was to understand the significance of cyclic nucleotide dependent protein kinases in health and disease. One major aspect is to identify the contributions from cGMP/PKG in the control of vascular smooth muscle contractility. Recently, our crystal structure of PKG (Osborne et al., Structure, 2011) has led us to the development of novel, cGMP-independent activators of PKG (S-tides) which are the focus of our current research. S-tides do not target endogenous cGMP turnover and thus may present an alternative therapeutic platform for the treatment of vascular disorders.
The control of vascular smooth muscle relaxation and the regulation of blood flow is tightly linked to the activity of cGMP-dependent protein kinase (PKG). However PKG itself has largely been ignored s a pharmaceutical target. In our recent work we developed S-tides, new class of PKG activators derived from a novel domain unique to this enzyme. These molecules differ fundamentally from all other existing drugs that target this pathway since they operate independently of cGMP. We are currently evaluating S-tides' functional significance biochemically and in vascular smooth muscle. The therapeutic potential of S-tides is immense, as they may modulate PKG activity with clinical benefit for vascular diseases, such as atherosclerosis, diabetes and hypertension.
* S-tides are a new class of molecule capable of selectively activating PKG 1α
* S-tides target PKG 1α and elevate the open probability of K+ channels (BK, KCa1.1)
* S-tides modulate vascular contractility via PKG 1α effects on BK channels
* S-tides dilate endothelium-denuded arteries that have exaggerated myogenic tone
We used a large variety of techniques from different fields on a regular basis:
Molecular Biology: cloning, mutagenesis, expression systems, fluorescent indicators
Protein-Biochemistry: molecular modeling, large scale bacterial and insect cell protein expression, purification methods, ligand-binding, enzyme kinetics
Biophysics: hydrodynamic properties, spectroscopic methods, crystallography, surface-plasmon-resonance
Cell Biology: mammalian transient transfections, dual-emission fluorescence microscopy, laser scanning confocal fluorescence microscopy
Physiology: pressurized small arteries, membrane potential measurements
Chemistry: combinatorial libraries, peptide synthesis, cyclic nucleotide analogs
We are in the process of closing this lab.