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Review
. 2006 Sep;5(9):755-68.
doi: 10.1038/nrd2038.

NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential

Affiliations
Review

NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential

Oleg V Evgenov et al. Nat Rev Drug Discov. 2006 Sep.

Abstract

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impaired bioavailability and/or responsiveness to endogenous NO has been implicated in the pathogenesis of cardiovascular and other diseases. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules, lack of response and the development of tolerance following prolonged administration. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages. Here we review the discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators (including YC-1, BAY 41-2272, BAY 41-8543, CFM-1571 and A-350619) and haem-independent sGC activators (including BAY 58-2667 and HMR-1766).

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Figures

Figure 1
Figure 1. The NO–sGC–cGMP signal transduction pathway and potential drug targets
Nitric oxide (NO) is synthesized enzymatically from the amino acid l-arginine by three isoforms of NO synthase (NOS), including endothelial NOS (eNOS). Minute amounts of endogenously produced or exogenously administered NO activate soluble guanylate cyclase (sGC), which converts GTP to cyclic GMP, mediating various physiological and tissue protective effects. Degradation of cGMP to GMP is catalysed by several phosphodiesterase (PDE) families. Excessive amounts of NO produced under pathological conditions associated with increased inflammation and oxidative stress react avidly with superoxide anion (O2), to form peroxynitrite (ONOO). Peroxynitrite, in concert with other oxidants, induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and activation of matrix metalloproteinases (MMP) and the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which ultimately leads to cellular dysfunction and death. NO–sGC–cGMP signalling can be compromised either by reducing the bioavailability of NO (for example, via chemical interaction of NO with O2) or by altering the redox state of sGC itself (for example, through oxidative stress or the action of peroxynitrite), thereby making it unresponsive to endogenous NO and NO-releasing drugs. Two novel drug classes seem to be able to overcome these obstacles: sGC stimulators (stimulate sGC directly and enhance sensitivity of the reduced enzyme to low levels of bioavailable NO) and sGC activators (activate the NO-unresponsive, haem-oxidized or haem-free enzyme). Other potential therapeutic approaches that modulate this pathway are also shown (dotted lines).
Figure 2
Figure 2. Homology model of the haem-binding domain of the human soluble guanylate cyclase (sGC) β-subunit
The model depicted is based on the recently resolved crystal structure of a prokaryotic haem-binding protein of Thermoanaerobacter tengcongensis with sequence homology to the sGC haem-binding domain,. Residues responsible for the coordination of the haem are shown in the enlargement on the right side. The axial haem ligand histidine-105 and the counterparts of the haem propionic acids tyrosine-135, serine-137 and arginine-139 comprise the unique sGC haem-binding motif Y-x-S-x-R (serine-137 was omitted for clarity),,.
Figure 3
Figure 3. Soluble guanylate cyclase (sGC) redox equilibrium
The figure illustrates the intracellular redox equilibrium of the two sGC redox states, nitric oxide (NO)-sensitive reduced (blue) and NO-insensitive oxidized sGC (pink). The equilibrium can be shifted by reactive oxygen species to the oxidized (ferric) state and by postulated but yet undiscovered reductases to the reduced (ferrous) form. Disequilibrium towards the oxidized NO-unresponsive enzyme exists under various pathophysiological conditions associated with oxidative stress. Haem-independent sGC activators such as BAY 58–2667 and HMR-1766 activate the oxidized or haem-deficient form. By contrast, haem-dependent stimulators YC-1, BAY 41-2272, BAY 41–8543, A-350619 and CFM-1571 can activate the reduced sGC and show a strong synergism when combined with NO.
Figure 4
Figure 4. NO–sGC–cGMP signalling in a blood vessel
l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO, which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Haem-dependent sGC stimulators and haem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. In contrast, organic nitrates require bioconversion to release NO, which is not implemented in platelets, leading to poor anti-aggregatory effect.

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