Guanylate kinase, inhibitors

GMP <2, 7> (<2> competitive inhibitor to dGMP [2] <7> non competitive with respect to MgATP because of the formation of an abortive complex guanylate kinase-MgATP "GMP [18]) [2, 18]... 

Nave, J.-F. Eschbach, A. Halazy, S. 9-(Phosphonoalkyl)guanine derivatives as substrates or inhibitors of guanylate kinase. Arch. Biochem. Biophys., 295, 253-257 (1992)... 

Acyclovir (ACV) is not a true nucleoside, because the guanine residue is attached to an open-chain structure, but it mimics deoxyribose well enough for the compound to be accepted as a substrate by a thymidine kinase specified by certain herpes-type viruses. The normal thymidine kinase in mammalian cells does not recognize ACV as a substrate, however, so only virus-infected cells convert ACV to its monophosphate. Once the first phosphate has been added, the second phosphate is added by cellular guanylate kinase several other cellular kinases can add the third phosphate. The triphosphate is a more potent inhibitor of the viral DNA polymerases than of cellular DNA polymerases and also inactivates the former but not the latter. The net result is that ACV has been an effective treatment of, and prophylaxis for, genital herpes. Also it can result in dramatic relief of pain associated with shingles caused by reactivation of latent varicella-zoster virus, and has been successful in many patients with herpes encephalitis. 

Several 9-(phosphonoalkyl)- and 9-(difluoroalkyl)-guanine derivatives (12, X = H or F) have been studied as potential inhibitors of guanylate kinase. The most pronounced effect was observed with n - 5 Phenoxymethylene bisphosphonates (13, where R R and R represent a variety of substituents) were prepared and found to act as inositol phosphatase inhibitors and antimanic agents some inhibited the enzyme with IC50 < 50 pmol 4-(Phosphonomethylphenoxy)-l-carbamoylazetidine-2-ones (14) inhibited human leukocyte elastase for 14 (R R = OEt = 1.2 x 10 moL s (ref. 38). 

The guanylate cyclase inhibitor LY83583 inhibited human alveolar macrophage spreading and staining for cGMP-dependent protein kinase at the cell periphery (Pryzwansky et al. 1995). 

NOS inhibitors, and the addition of excess L-arginine reverses this blockade (Hirsch et al., 1993). NO may stimulate the release of neurotransmitters by activation of guanylate cyclase and elevation of intracellular cGMP, which activates cGMP-dependent protein kinases to augment the phosphorylation of synaptic vesicle proteins associated with neurotransmitter release. 

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