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      Repurposing soluble guanylate cyclase stimulators from one to another isoform within the ROCG signalling module

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            Abstract

            Currently, most disease treatments are symptom- based without any mechanistic basis, leading to unmet medical need and high numbers needed to treat. Identifying the underlying disease mechanisms is key for precise treatment and drug repurposing. One example is an impaired signalling network related to reactive oxygen species ( ROS) involvement with cGMP signalling (the ROCG disease module). This disease module is relevant for a heterogenous cluster of neurological, metabolic, and pulmonary disease phenotypes 1. ROS formation by NADPH oxidases (NOX) can affect the ROCG module in several ways: (i) scavenging of NO and further increase of ROS production, (ii) NO synthase (NOS) uncoupling, and (iii) formation of insensitive to NO oxidised/heme-free soluble guanylate cyclase (sGC) 2, 3. By targeting different parts of this pathway with a network pharmacology approach, we could restore the physiological state in a highly synergistic manner. Such drugs are also already available in the clinic. For example, Riociguat is registered for pulmonary arterial hypertension and belongs to the so-called sGC stimulators (sGCs) which are thought to act exclusively on NO-sensitive sGC 3. Here, we show that sGCs are also able to stimulate the oxidised/heme-free form of sGC, the so-called apo-sGC. Moreover, we show that sGCs combined with sGC activators (registered as activators of apo-sGC) yield additive or supra-additive effects on apo-sGC. This data suggests that sGCs can be repurposed for cases where apo-sGC is the primary form of the enzyme, such as overproduction of reactive oxygen species. A promising example is acute ischemic stroke 1. For this indication, three drugs targeting the ROCG network are being repurposed: (i) riociguat, targeting almost exclusively apo-sGC, (ii) propylthiouracil, registered as an antithyroid drug but also acting as a NOS inhibitor 4, and (iii) perphenazine, an antipsychotic drug acting as an NOX inhibitor 5 (REPO-STROKE II, EudraCT no. 2019– 000474-31). In conclusion, our data suggest that drug repurposing for different target proteins and indications can be easily translated to direct patient benefit.

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            Author and article information

            Conference
            ScienceOpen
            29 August 2022
            Affiliations
            [1 ] Department of Pharmacology and Personalized Medicine, MeHNS, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht, 6229 ER, the Netherlands.
            [2 ] Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
            [3 ] Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig, Germany
            [4 ] Department of Neurology and Center for Translational Neuro- and Behavioural Sciences (C-TNBS), University Clinic Essen, Essen, Germany.
            [5 ] Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
            [6 ] H.M. Pharma Consultancy, Enenkelstrasse 28/32, A-1160, Vienna, Austria
            Author notes
            Author information
            https://orcid.org/0000-0002-1667-0266
            Article
            10.14293/S2199-1006.1.SOR-.PPPUX7CJ.v1
            33de3057-d5d7-47aa-821e-b3f0803d0888

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            RExPO22
            Maastricht, Netherlands
            2-3 September, 2022
            History
            : 29 August 2022
            Product

            ScienceOpen


            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Drug repurposing, network pharmacology, sGC stimulators, stroke

            References

            1. Langhauser Friederike, Casas Ana I., Dao Vu-Thao-Vi, Guney Emre, Menche Jörg, Geuss Eva, Kleikers Pamela W. M., López Manuela G., Barabási Albert-L., Kleinschnitz Christoph, Schmidt Harald H. H. W.. A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection. npj Systems Biology and Applications. Vol. 4(1)2018. Springer Science and Business Media LLC. [Cross Ref]

            2. Casas Ana I., Hassan Ahmed A., Larsen Simon J., Gomez-Rangel Vanessa, Elbatreek Mahmoud, Kleikers Pamela W. M., Guney Emre, Egea Javier, López Manuela G., Baumbach Jan, Schmidt Harald H. H. W.. From single drug targets to synergistic network pharmacology in ischemic stroke. Proceedings of the National Academy of Sciences. Vol. 116(14):7129–7136. 2019. Proceedings of the National Academy of Sciences. [Cross Ref]

            3. Petraina Alexandra, Nogales Cristian, Krahn Thomas, Mucke Hermann, Lüscher Thomas F, Fischmeister Rodolphe, Kass David A, Burnett John C, Hobbs Adrian J, Schmidt Harald H H W. Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology. Cardiovascular Research. Vol. 118(9):2085–2102. 2022. Oxford University Press (OUP). [Cross Ref]

            4. Palumbo Anna, d'Ischia Marco. Thiouracil Antithyroid Drugs as a New Class of Neuronal Nitric Oxide Synthase Inhibitors. Biochemical and Biophysical Research Communications. Vol. 282(3):793–797. 2001. Elsevier BV. [Cross Ref]

            5. Elbatreek Mahmoud H., Mucke Hermann, Schmidt Harald H. H. W.. NOX Inhibitors: From Bench to Naxibs to BedsideReactive Oxygen Species. p. 145–168. 2020. Springer International Publishing. [Cross Ref]

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