Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19

Autor: Laurence Laigle, Isabelle Dupin-Roger, Antoine Hamon, Audrey Aussy, Emiko Desvaux, Philippe Moingeon, Jack Swindle, Jessica Laplume, Pierre Jean-François, Perrine Soret, Mickaël Guedj, Bastien Chassagnol, Cheïma Boudjeniba, Sandra Hubert
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
RNA viruses
Viral Diseases
Pulmonology
Physiology
Coronaviruses
Cancer Treatment
Drug research and development
Bioinformatics
0302 clinical medicine
Medical Conditions
Clinical trials
Immune Physiology
Interleukin 23
Medicine and Health Sciences
Medicine
Alarmins
Immune Response
Repurposing
Pathology and laboratory medicine
media_common
Innate Immune System
Multidisciplinary
Medical microbiology
Drug repositioning
Cytokine release syndrome
Infectious Diseases
Oncology
030220 oncology & carcinogenesis
Viruses
Cytokines
medicine.symptom
SARS CoV 2
Pathogens
Phase II clinical investigation
Research Article
Drug
SARS coronavirus
media_common.quotation_subject
Inflammatory Diseases
Science
Immunology
Inflammation
Cytokine Therapy
Antiviral Agents
Microbiology
03 medical and health sciences
Respiratory Disorders
Immune system
Signs and Symptoms
Humans
Pharmacology
business.industry
Drug Repositioning
Organisms
Viral pathogens
COVID-19
Biology and Life Sciences
Covid 19
Pneumonia
Molecular Development
medicine.disease
Microbial pathogens
Research and analysis methods
030104 developmental biology
Immune System
Clinical medicine
Respiratory Infections
business
Cytokine storm
Developmental Biology
Zdroj: PLoS ONE, Vol 16, Iss 7, p e0254374 (2021)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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