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

Stebbing, Justin ; Krishnan, Venkatesh ; Bono, Stephanie ; Ottaviani, Silvia ; Casalini, Giacomo ; Richardson, Peter J ; Monteil, Vanessa ; Lauschke, Volker M ; Mirazimi, Ali ; Youhanna, Sonia ; Tan, Yee‐Joo ; Baldanti, Fausto ; Sarasini, Antonella ; Terres, Jorge A Ross ; Nickoloff, Brian J ; Higgs, Richard E ; Rocha, Guilherme ; Byers, Nicole L ; Schlichting, Douglas E ; Nirula, Ajay ; Cardoso, Anabela ; Corbellino, Mario

EMBO molecular medicine, 2020-08, Vol.12 (8), p.e12697-n/a [Periódico revisado por pares]

England: John Wiley & Sons, Inc

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Título:
Mechanism of baricitinib supports artificial intelligence‐predicted testing in COVID‐19 patients
Autor: Stebbing, Justin ; Krishnan, Venkatesh ; Bono, Stephanie ; Ottaviani, Silvia ; Casalini, Giacomo ; Richardson, Peter J ; Monteil, Vanessa ; Lauschke, Volker M ; Mirazimi, Ali ; Youhanna, Sonia ; Tan, Yee‐Joo ; Baldanti, Fausto ; Sarasini, Antonella ; Terres, Jorge A Ross ; Nickoloff, Brian J ; Higgs, Richard E ; Rocha, Guilherme ; Byers, Nicole L ; Schlichting, Douglas E ; Nirula, Ajay ; Cardoso, Anabela ; Corbellino, Mario
Assuntos: Adult ; Aged ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; anti‐cytokine ; anti‐viral ; Artificial Intelligence ; Azetidines - pharmacokinetics ; Azetidines - pharmacology ; Azetidines - therapeutic use ; baricitinib ; Betacoronavirus ; Cardiovascular disease ; case series ; Chronic obstructive pulmonary disease ; Clinical trials ; Coronavirus Infections - drug therapy ; Coronaviruses ; COVID-19 ; Cytokines ; Cytokines - antagonists & inhibitors ; Disease transmission ; Drug Evaluation, Preclinical ; Drug Repositioning ; Drugs ; Female ; Hospitalization ; Humans ; Infections ; Infectivity ; Inflammation ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Janus kinase ; Janus kinase 2 ; Kinases ; Leukocytes - drug effects ; Liver ; Male ; Medicin och hälsovetenskap ; Middle Aged ; Mortality ; Pandemics ; Patients ; Pharmacokinetics ; Pneumonia ; Pneumonia, Viral - drug therapy ; Propagation ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Public health ; Rheumatoid arthritis ; SARS-CoV-2 ; Severe acute respiratory syndrome coronavirus 2 ; Spheroids ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - virology ; Subpopulations ; Sulfonamides - pharmacokinetics ; Sulfonamides - pharmacology ; Sulfonamides - therapeutic use
É parte de: EMBO molecular medicine, 2020-08, Vol.12 (8), p.e12697-n/a
Notas: See also: MB Schultz et al (August 2020)
These authors contributed equally to this work as senior authors
Sacco Baricitinib Study Group members are listed in the Appendix
These authors contributed equally to this work as first authors
Descrição: 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 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 support its assessment in randomized trials in hospitalized COVID‐19 patients. Synopsis This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients. Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor used to treat rheumatoid arthritis, was hypothesised using AI to be useful in COVID‐19. Baricitinib‐mediated inhibition of numb associated kinases utilized by SARS‐CoV‐2 for its propagation, led to reduced viral infectivity in primary liver spheroids. Baricitinib reduces levels of cytokines implicated in COVID‐19 and inhibits their signaling. In 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. This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.
Editor: England: John Wiley & Sons, Inc
Idioma: Inglês

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

England: John Wiley & Sons, Inc

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