Soluble guanylate cyclase (sGC) modulators are small-molecule drugs that bind sGC and enhance nitric oxide (NO)-mediated cGMP signalling. The suffix “ciguat” is the unique identifier for this drug class. There are two types of "ciguats"; NOsGC stimulators, which act through allosteric regulation and NOsGC activators, which occupy the heme binding site and work additively with NO (Kraehling & Sessa 2017).

In the early 2000s, cinaciguat (BAY 58-2667) was identified as a novel NOsGC activator (Stasch et al. 2002). Cinaciguat has been shown to unload the heart in patients with acute decompensated heart failure (ADHF). However, high doses of cinaciguat are associated with hypotension (Erdmann et al. 2013).

Soluble guanylate cyclase (sGC) modulators are small-molecule drugs that bind sGC and enhance nitric oxide (NO)-mediated cGMP signalling, resulting in vasodilation and inhibition of platelet aggregation. The suffix “ciguat” is the unique identifier for this drug class. There are two types of "ciguats"; NOsGC stimulators, which act through allosteric regulation and NOsGC activators, which occupy the heme binding site and work additively with NO (Kraehling & Sessa 2017).

NOsGC stimulators activate sGC independently of NO. This was demonstrated in human platelets by the first allosteric activator lificiguat (YC-1), a benzyl indazol derivative (Friebe et al. 1998). Lificiguat, synergistically with NO, stimulates sGC activity 200-800 fold to result in inhibition of platelet aggregation. A regulatory site on sGC was discovered to be the probable binding site (C239 and C244 regions) for sGC stimulators using the pyrazolopyridine BAY 41-2272, a lificiguat analog (Stasch et al. 2001). BAY 41-2272 induces vasodilation without developing nitrate tolerance, possesses antiplatelet activity and reduces mortality. Optimisation experiments on lificiguat led to the development of riociguat (BAY 63-252, Adempas). Riociguat, activates NOsGC 70-fold at therapeutic concentrations and is the only "ciguat" so far to be approved for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) (Schermuly et al. 2008).

Another NOsGC stimulator, vericiguat, shows an optimized pharmacokinetic profile and allows a once daily dosing regimen, unlike riociguat (3 times a day) (Breitenstein et al. 2017). Vericiguat is in clinical trials to determine its efficacy in heart failure, in patients with chronic failure and reduced ejection fraction (Gheorghiade et al. 2015). Praliciguat (IW-1973) is a novel clinical-stage NOsGC stimulator under clinical investigation for the treatment of heart failure with preserved ejection fraction and diabetic nephropathy (Tobin et al. 2018, Breitenstein et al. 2017).

Mammalian CD59, the major inhibitor of the complement membrane attack complex (MAC), is an 18-20 kDa glycoprotein, linked to the membrane via a glycosylphosphatidylinositol (GPI)-anchor. It interacts with complement components C8 and C9 during assembly of the membrane attack complex (MAC) and inhibits C9 polymerization, thus preventing the formation of MAC (Lehto T and Meri S. 1993; Rollins SA et al. 1991).

RT-PCR analysis revealed that chicken CD59 mRNA is expressed in brain, heart, lung, spleen, liver, stomach and kidney. It is fully expressed in the following developmental stages: whole embryo 4- and 6-day old, embryo liver of 12- and 17-day old and neonate 2- and 5-day old (Mikrou A and Zarkadis IK 2010).

The module represents hypothetical chicken CD59, which may not have an identifier assigned in any of genome databases. The binding of chicken CD59 to MAC has not been verified experimentally but is inferred from properties of the human proteins.