Adenosine analogue-oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIalpha)

Biochim Biophys Acta. 2010 Sep;1804(9):1857-68. doi: 10.1016/j.bbapap.2010.04.007. Epub 2010 Apr 18.


Introduction: Type I cGMP-dependent protein kinase (PKGIalpha) belongs to the family of cyclic nucleotide-dependent protein kinases and is one of the main effectors of cGMP. PKGIalpha is involved in regulation of cardiac contractility, vasorelaxation, and blood pressure; hence, the development of potent modulators of PKGIalpha would lead to advances in the treatment of a variety of cardiovascular diseases.

Aim: Representatives of ARC-type compounds previously characterized as potent inhibitors and high-affinity fluorescent probes of PKA catalytic subunit (PKAc) were tested towards PKGIalpha to determine that ARCs could serve as activity regulators and sensors for the latter protein kinase both in vitro and in complex biological systems.

Results: Structure-activity profiling of ARCs with PKGIalpha in vitro demonstrated both similarities as well as differences to corresponding profiling with PKAc, whereas ARC-903 and ARC-668 revealed low nanomolar displacement constants and inhibition IC(50) values with both cyclic nucleotide-dependent kinases. The ability of ARC-based fluorescent probes to penetrate cell plasma membrane was demonstrated in the smooth muscle tissue of rat cerebellum isolated arteries, and the compound with the highest affinity in vitro (ARC-903) showed also potential for in vivo applications, fully abolishing the PKG1alpha-induced vasodilation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / chemistry*
  • Animals
  • Arginine / chemistry*
  • Cerebral Arteries / cytology
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / metabolism
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fluorescence
  • Fluorescent Dyes*
  • Humans
  • Muscle, Smooth, Vascular / drug effects*
  • Rats
  • Vasodilation / drug effects


  • Enzyme Inhibitors
  • Fluorescent Dyes
  • Arginine
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • PRKG1 protein, human
  • Cyclic GMP
  • Adenosine