cGMP-Dependent Protein Kinase Inhibitors in Health and Disease

Abstract

cGMP-dependent protein kinases (PKG) exhibit diverse physiological functions in the mammalian system e.g., in vascular and gastrointestinal smooth muscles, in platelets, in kidney, in bone growth, nociception and in the central nervous system. Furthermore, PKG were found in insects and in the malaria parasite Plasmodium falciparum. Two different genes of PKG exist: a) the PKG-I gene that is expressed as cytosolic PKG-Iα or PKG-Iβ isoform, and b) the PKG-II gene, which expresses the membrane associated PKG-II protein. The enzyme kinetics, the localization and the substrates of these PKG enzymes differ utilizing different physiological functions. Various inhibitors of PKG were developed directed against diverse functional regions of the kinase. These inhibitors of PKG have been used to analyse the specific functions of these enzymes. The review article will summarize these different inhibitors regarding their specificity and their present applications in vitro and in vivo. Furthermore, it will be discussed that the distinct inhibition of the PKG enzymes could be used as a valuable pharmacological target e.g., in the treatment of cardiovascular diseases, diarrhea, cancer or malaria.

Synthesis and Characterization of 8-Nitroguanosine 3′,5′-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase G1α

“…Several types of PKG inhibitors have been developed to target different sites and domains in the enzyme. 4,5) Cyclic nucleotide analogues such as Rp-cGMPS bind to the cGMP-binding sites without induction of a conformational change in the enzyme.…”

“…4) DT inhibitors are peptide inhibitors that target the substratebinding region of the enzyme. 4) Monophosphorothioate analogues of cGMP (cGMPS) have dual effects on PKG1 activation that depend on the stereochemistry of the compounds.…”

“…The lipophilicity of PKG inhibitors has been thought to be an important determinant of the inhibitory potentials of PKG inhibitors in cell and tissue experiments. 4,5) We previously determined the lipophilicity of 8-nitro-cGMP and 8-bromocGMP on the basis of octanol/water partition coefficient measurements, and we found 8-nitro-cGMP to be less lipophilic than 8-bromo-cGMP. 12) Consistent with this result, we found that tissue levels of Rp-8-nitro-cGMPS were lower than those of Rp-8-bromo-cGMPS after mouse aortic rings were incubated with those inhibitors (Fig.…”

“…4,5) The Rp-diastereomers of analogues of guanosine 3′,5′-cyclic monophosphorothioate (Rp-cGMPS) have long been studied as competitive inhibitors of PKG1α. 4,5) They bind to PKG but apparently do not evoke conformational changes of the enzyme required for its activation. 6) Rp-8-Bromoguanosine 3′,5′-cyclic monophosphorothioate (Rp-8-bromo-cGMPS) is a widely used PKG inhibitor in signal transduction research.…”

“…Accumulating evidence suggested that PKG inhibition may be a potential target in the treatment of certain diseases such as bacterial toxin-induced diarrhea and cancers of the lung, colon, breast, and ovary. 4,5) We discovered endogenous formation of the nitrated cGMP derivative 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) under conditions associated with excess production of both nitric oxide (NO) and reactive oxygen species in mammalian cells [7][8][9][10][11][12][13][14][15][16][17] as well as in plants. 18,19) Biochemical analyses revealed that 8-nitro-cGMP can activate PKG1α to a similar extent as native cGMP can.…”