Mechanism of baricitinib supports artificial intelligence‐predicted testing in COVID ‐19 patients

Autor: Volker M. Lauschke, Guilherme Rocha, Jorge A. Ross Terres, Venkatesh Krishnan, Sonia Youhanna, Justin Stebbing, Vanessa Monteil, Silvia Ottaviani, Antonella Sarasini, Anabela Cardoso, Yee-Joo Tan, Fausto Baldanti, Brian J. Nickoloff, Stephanie de Bono, Nicole L. Byers, Mario Corbellino, Ali Mirazimi, Peter J. Richardson, Douglas E Schlichting, Richard E. Higgs, Giacomo Casalini, Ajay Nirula
Přispěvatelé: National Institute for Health Research
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Medicine (General)
Drug Evaluation
Preclinical
Sacco Baricitinib Study Group
QH426-470
Research & Experimental Medicine
anti-cytokine
0302 clinical medicine
Baricitinib
Leukocytes
Medicine
11 Medical and Health Sciences
Infectivity
Sulfonamides
Kinase
case series
Intracellular Signaling Peptides and Proteins
AAK1
Articles
Middle Aged
Protein-Serine-Threonine Kinases
Drug repositioning
CLATHRIN
Medicine
Research & Experimental
Liver
SAFETY
Rheumatoid arthritis
ENTRY
Cytokines
Molecular Medicine
Female
Coronavirus Infections
Life Sciences & Biomedicine
Viral load
anti-viral
Adult
Pneumonia
Viral
anti‐cytokine
Antiviral Agents
Article
Betacoronavirus
03 medical and health sciences
R5-920
Pharmacokinetics
COVID‐19
Artificial Intelligence
Spheroids
Cellular
Genetics
Humans
anti‐viral
Pandemics
Protein Kinase Inhibitors
Aged
Science & Technology
SARS-CoV-2
business.industry
Drug Repositioning
COVID-19
06 Biological Sciences
medicine.disease
030104 developmental biology
Purines
CELLS
Pyrazoles
Azetidines
Artificial intelligence
business
Janus kinase
030217 neurology & neurosurgery
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 12, Iss 8, Pp n/a-n/a (2020)
ISSN: 1757-4684
1757-4676
Popis: Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI)‐algorithms, to be useful for COVID‐19 infection via a proposed anti‐cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID‐19 infection. We validated the AI‐predicted biochemical inhibitory effects of baricitinib on human numb‐associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Collectively, these data support further evaluation of the anti‐cytokine and anti‐viral activity of baricitinib and supports its assessment in randomized trials in hospitalized COVID‐19 patients.
Databáze: OpenAIRE
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