A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection

A cGMP-related phenotype cluster within the human diseasome suggests a predominant neurological relevance. a shows the human disease network2 where nodes represent disease phenotypes that are linked if they share a genetic association. Different colors indicate different organ systems. Within the network a local cluster contains several diseases phenotypes therapeutically amenable to drugs modulating cGMP forming or cGMP metabolizing enzymes. This is magnified in b and reveals additional metabolic (blue: DM, diabetes mellitus; OB, obesity), pulmonary (brown: AB, asthma) and neurological (red: ST, stroke; AD, Alzheimer’s disease; MG, migraine; DE, dementia; PD, Parkinson’s disease) linked disease phenotypes. For each disease we included in the squares those drugs that are either in the clinic or in late stage clinical development (sGCa, apo-sGC activators; sGCs, sGC stimulators; NOd, NO donors; ARNi; neprilysin inhibitors; PDEi, phosphodiesterase inhibitors). Panels indicate common associated genes c, physical interactions between affected proteins d, shared symptoms e and elevated comorbidity f. When analyzing the interactome of sGC g, its subunits (orange) are significantly closer to neurological diseases (red) than random expectation and surprisingly more distant to cardiovascular applications (dark blue) that current clinical practice (Table (Table22