Abstract:Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology.
“…Investigation of cGMP turnover by cyclases and phosphodiesterases as well as knowledge of cGMP effectors and their downstream targets are of key importance to understand the molecular physiology and pathophysiology of this signaling cascade. Knowledge of basic mechanisms is, thus, a prerequisite for the development of drugs within this pathway which have substantial therapeutic implications and help to improve the life of patients (Oettrich et al 2016 ; Buglioni and Burnett 2016 ).…”
Although the Nobel Prize for the discovery of nitric oxide (NO) dates back almost 20 years now, the knowledge about cGMP signaling is still constantly increasing. It looks even so that our understanding of the role of the soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC) in health and disease is in many aspects at the beginning and far from being understood. This holds even true for the therapeutic impact of innovative drugs acting on both the NO/sGC and the pGC pathways. Since cGMP, as second messenger, is involved in the pathogenesis of numerous diseases within the cardiovascular, pulmonary, renal, and endocrine systems and also plays a role in neuronal, sensory, and tumor processes, drug applications might be quite broad. On the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics. All aspects of cGMP research from the basic understanding of cGMP signaling to clinical applicability were discussed in depth. In addition, present and future therapeutic applications of cGMP-modulating pharmacotherapy were presented (http://www.cyclicgmp.net/index.html).
“…Investigation of cGMP turnover by cyclases and phosphodiesterases as well as knowledge of cGMP effectors and their downstream targets are of key importance to understand the molecular physiology and pathophysiology of this signaling cascade. Knowledge of basic mechanisms is, thus, a prerequisite for the development of drugs within this pathway which have substantial therapeutic implications and help to improve the life of patients (Oettrich et al 2016 ; Buglioni and Burnett 2016 ).…”
Although the Nobel Prize for the discovery of nitric oxide (NO) dates back almost 20 years now, the knowledge about cGMP signaling is still constantly increasing. It looks even so that our understanding of the role of the soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC) in health and disease is in many aspects at the beginning and far from being understood. This holds even true for the therapeutic impact of innovative drugs acting on both the NO/sGC and the pGC pathways. Since cGMP, as second messenger, is involved in the pathogenesis of numerous diseases within the cardiovascular, pulmonary, renal, and endocrine systems and also plays a role in neuronal, sensory, and tumor processes, drug applications might be quite broad. On the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics. All aspects of cGMP research from the basic understanding of cGMP signaling to clinical applicability were discussed in depth. In addition, present and future therapeutic applications of cGMP-modulating pharmacotherapy were presented (http://www.cyclicgmp.net/index.html).
“…Taken together, these common treatments suggest a prominent role of cGMP signaling in these disease phenotypes, mostly targeting the NO-responsive sGC. 6 All drugs currently targeting cGMP clinically—NO donors, sGC stimulators and sGC activators—have almost exclusively cardio-pulmonary indications 8 such as coronary artery disease, 9 hypertensive crisis 10 and pulmonary hypertension, 11 although some of them are currently being tested in other diseases such as cystic fibrosis (NCT02170025), systemic scleroderma (NCT02283762) 5 and animal models of kidney diseases. 12 Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Using a data-driven approach, disease–disease networks (diseosome) have been constructed in which diseases are linked based on common molecular or regulatory mechanisms, 2 such as shared genetic associations, 2 protein interactions 3 , 4 or gene–disease interactions. 5 These diseasomes exhibit local clusters of diseases whose molecular relationships are well understood, but also unexpected clusters of surprisingly heterogeneous diseases. 3 Such clustering of disease phenotypes is likely due to underlying hidden common pathomechanisms.…”
Section: Introductionmentioning
confidence: 99%
“…Genetic evidence points to cGMP signaling as being part of its underlying pathomechanism. 5 , 6 We then inquire in a non-hypothesis-based manner using disease–disease networks based on common genetic origins, common protein interactions between disease genes, shared disease symptoms and disease co-morbidity for possible drug repurposing of cGMP modulators within this cluster.…”
Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.
“…cGMP is implicated in various diseases, and multiple medications that increase the cGMP concentration are already on the market for use in humans, such as the PDE5 inhibitor Sildenafil for erectile dysfunction, the guanylyl cyclase C agonist Linaclotide for chronic idiopathic constipation and irritable bowel syndrome, and the NO-GC stimulator Riociguat for certain forms of pulmonary hypertension [16,17,18,19]. Given the druggability of the cGMP pathway, it would be informative to further elucidate the cGMP signaling pathway in the nervous system.…”
Dysfunctions of NO-cGMP signaling have been implicated in various neurological disorders. We have studied the potential crosstalk of cGMP and Ca2+ signaling in cerebellar granule neurons (CGNs) by simultaneous real-time imaging of these second messengers in living cells. The NO donor DEA/NO evoked cGMP signals in the granule cell layer of acute cerebellar slices from transgenic mice expressing a cGMP sensor protein. cGMP and Ca2+ dynamics were visualized in individual CGNs in primary cultures prepared from 7-day-old cGMP sensor mice. DEA/NO increased the intracellular cGMP concentration and augmented glutamate-induced Ca2+ transients. These effects of DEA/NO were absent in CGNs isolated from knockout mice lacking NO-sensitive guanylyl cyclase. Furthermore, application of the cGMP analogues 8-Br-cGMP and 8-pCPT-cGMP, which activate cGMP effector proteins such as cyclic nucleotide-gated cation channels and cGMP-dependent protein kinases (cGKs), also potentiated glutamate-induced Ca2+ transients. Western blot analysis failed to detect cGK type I or II in our primary CGNs. The addition of phosphodiesterase (PDE) inhibitors during cGMP imaging showed that CGNs degrade cGMP mainly via Zaprinast-sensitive PDEs, most likely PDE5 and/or PDE10, but not via PDE1, 2, or 3. In sum, these data delineate a cGK-independent NO-cGMP signaling cascade that increases glutamate-induced Ca2+ signaling in CGNs. This cGMP–Ca2+ crosstalk likely affects neurotransmitter-stimulated functions of CGNs.
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