From single drug targets to synergistic network pharmacology in ischemic stroke

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Casas, Ana I.
  • dc.contributor.author Hassan, Ahmed
  • dc.contributor.author Larsen, Simon J.
  • dc.contributor.author Gomez-Rangel, Vanessa
  • dc.contributor.author Elbatreek, Mahmoud
  • dc.contributor.author Kleikers, Pamela W. M.
  • dc.contributor.author Guney, Emre
  • dc.contributor.author Egea, Javier
  • dc.contributor.author López, Manuela G.
  • dc.contributor.author Baumbach, Jan
  • dc.contributor.author Schmidt, Harald H.H.W.
  • dc.date.accessioned 2020-04-01T08:39:09Z
  • dc.date.available 2020-04-01T08:39:09Z
  • dc.date.issued 2019
  • dc.description.abstract Drug discovery faces an efficacy crisis to which ineffective mainly single-target and symptom-based rather than mechanistic approaches have contributed. We here explore a mechanism-based disease definition for network pharmacology. Beginning with a primary causal target, we extend this to a second using guilt-by-association analysis. We then validate our prediction and explore synergy using both cellular in vitro and mouse in vivo models. As a disease model we chose ischemic stroke, one of the highest unmet medical need indications in medicine, and reactive oxygen species forming NADPH oxidase type 4 (Nox4) as a primary causal therapeutic target. For network analysis, we use classical protein-protein interactions but also metabolite-dependent interactions. Based on this protein-metabolite network, we conduct a gene ontology-based semantic similarity ranking to find suitable synergistic cotargets for network pharmacology. We identify the nitric oxide synthase (Nos1 to 3) gene family as the closest target to Nox4 Indeed, when combining a NOS and a NOX inhibitor at subthreshold concentrations, we observe pharmacological synergy as evidenced by reduced cell death, reduced infarct size, stabilized blood-brain barrier, reduced reoxygenation-induced leakage, and preserved neuromotor function, all in a supraadditive manner. Thus, protein-metabolite network analysis, for example guilt by association, can predict and pair synergistic mechanistic disease targets for systems medicine-driven network pharmacology. Such approaches may in the future reduce the risk of failure in single-target and symptom-based drug discovery and therapy.
  • dc.description.sponsorship This study was supported by the ERC (Advanced Investigator Grant 294683/RadMed and Proof-of-Concept Grant 737586/SAVEBRAIN, both to H.H.H.W.S.), Spanish Ministry of Economy and Competence (SAF2015-63935R to M.G.L.), Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional) (Programa Miguel Servet: CP14/00008, PI16/00735), Fundación Mutua Madrileña (J.E.), short-term scientific missions by the COST Actions EU-ROS and OpenMultiMed, and Kootstra Talented Fellowship (UM) (to A.I.C.). J.B.’s work was financially supported by VILLUM Young Investigator Grant 13154. J.B. and H.H.H.W.S. also received support from H2020 Project 777111-REPO-TRIAL.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Casas AI, Hassan AA, Larsen SJ, Gomez-Rangel V, Elbatreek M, Kleikers PWM, et al. From single drug targets to synergistic network pharmacology in ischemic stroke. Proc Natl Acad Sci U S A. 2019 Apr 2; 116(14): 7129-36. DOI: 10.1073/pnas.1820799116
  • dc.identifier.doi http://dx.doi.org/10.1073/pnas.1820799116
  • dc.identifier.issn 0027-8424
  • dc.identifier.uri http://hdl.handle.net/10230/44131
  • dc.language.iso eng
  • dc.publisher National Academy of Sciences
  • dc.relation.ispartof Proceedings of the National Academy of Sciences of the United States of America. 2019 Apr 2;116(14):7129-36
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-63935R
  • dc.rights © National Academy of Sciences © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). https://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword NOX4
  • dc.subject.keyword Network analysis
  • dc.subject.keyword Network pharmacology
  • dc.subject.keyword Stroke
  • dc.title From single drug targets to synergistic network pharmacology in ischemic stroke
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Hospital del Mar Research Institute)
Articles (Departament de Medicina i Ciències de la Vida)