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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalEMBO Molecular Medicine
DOIs
Publication statusAccepted/In press - Jan 1 2020

Keywords

  • anti-cytokine
  • anti-viral
  • baricitinib
  • case series
  • COVID-19

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients'. Together they form a unique fingerprint.

  • Cite this

    Stebbing, J., Krishnan, V., de Bono, S., Ottaviani, S., Casalini, G., Richardson, P. J., Monteil, V., Lauschke, V. M., Mirazimi, A., Youhanna, S., Tan, Y. J., Baldanti, F., Sarasini, A., Terres, J. A. R., Nickoloff, B. J., Higgs, R. E., Rocha, G., Byers, N. L., Schlichting, D. E., ... Corbellino, M. (Accepted/In press). Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.202012697