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

EMBO Mol Med. 2020 Aug 7;12(8):e12697. doi: 10.15252/emmm.202012697. Epub 2020 Jun 24.

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.

Keywords: COVID-19; anti-cytokine; anti-viral; baricitinib; case series.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Artificial Intelligence*
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology*
  • Azetidines / therapeutic use
  • Betacoronavirus*
  • COVID-19
  • Coronavirus Infections / drug therapy*
  • Cytokines / antagonists & inhibitors
  • Drug Evaluation, Preclinical
  • Drug Repositioning
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Leukocytes / drug effects
  • Liver
  • Male
  • Middle Aged
  • Pandemics*
  • Pneumonia, Viral / drug therapy*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • SARS-CoV-2
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / virology
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use

Substances

  • Antiviral Agents
  • Azetidines
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Protein-Serine-Threonine Kinases
  • baricitinib

Supplementary concepts

  • COVID-19 drug treatment