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NPJ Syst Biol Appl. 2018 Feb 5;4:8. doi: 10.1038/s41540-017-0039-7. eCollection 2018.

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

Author information

1
1Department of Neurology, University Hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.
2
2Department of Neurology, University Hospital Essen, Hufelandstraße 55, D-45147 Essen, Germany.
3
3Department of Pharmacology and Personalised Medicine, CARIM, FHML, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
4
4Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo s/n, 28029 Madrid, Spain.
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5Center for Complex Network Research (CCNR) and Department of Physics, Northeastern University, Boston, MA 02115 USA.
6
6Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
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7CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria.
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8Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
9
9Center for Network Science, Central European University, Nador u. 9, 1051 Budapest, Hungary.
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Contributed equally

Abstract

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.

Conflict of interest statement

H.H.H.W.S. receive a research grant from Bayer Healthcare, the patent owner of BAY58-2667 and BAY60-2770. The remaining authors declare no competing financial interests.

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