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Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19.
PLoS One. 2021; 16(7):e0254374.Plos

Abstract

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1β, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.

Authors+Show Affiliations

Servier, Research and Development, Suresnes Cedex, France.Lincoln, Research and Development, Boulogne-Billancourt Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Lincoln, Research and Development, Boulogne-Billancourt Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.Servier, Research and Development, Suresnes Cedex, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34293006

Citation

Desvaux, Emiko, et al. "Network-based Repurposing Identifies Anti-alarmins as Drug Candidates to Control Severe Lung Inflammation in COVID-19." PloS One, vol. 16, no. 7, 2021, pp. e0254374.
Desvaux E, Hamon A, Hubert S, et al. Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19. PLoS One. 2021;16(7):e0254374.
Desvaux, E., Hamon, A., Hubert, S., Boudjeniba, C., Chassagnol, B., Swindle, J., Aussy, A., Laigle, L., Laplume, J., Soret, P., Jean-François, P., Dupin-Roger, I., Guedj, M., & Moingeon, P. (2021). Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19. PloS One, 16(7), e0254374. https://doi.org/10.1371/journal.pone.0254374
Desvaux E, et al. Network-based Repurposing Identifies Anti-alarmins as Drug Candidates to Control Severe Lung Inflammation in COVID-19. PLoS One. 2021;16(7):e0254374. PubMed PMID: 34293006.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19. AU - Desvaux,Emiko, AU - Hamon,Antoine, AU - Hubert,Sandra, AU - Boudjeniba,Cheïma, AU - Chassagnol,Bastien, AU - Swindle,Jack, AU - Aussy,Audrey, AU - Laigle,Laurence, AU - Laplume,Jessica, AU - Soret,Perrine, AU - Jean-François,Pierre, AU - Dupin-Roger,Isabelle, AU - Guedj,Mickaël, AU - Moingeon,Philippe, Y1 - 2021/07/22/ PY - 2021/03/05/received PY - 2021/06/24/accepted PY - 2021/7/22/entrez PY - 2021/7/23/pubmed PY - 2021/8/5/medline SP - e0254374 EP - e0254374 JF - PloS one JO - PLoS One VL - 16 IS - 7 N2 - While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1β, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/34293006/Network-based_repurposing_identifies_anti-alarmins_as_drug_candidates_to_control_severe_lung_inflammation_in_COVID-19. L2 - https://dx.plos.org/10.1371/journal.pone.0254374 DB - PRIME DP - Unbound Medicine ER -