Small-molecule screening identifies Syk kinase inhibition and rutaecarpine as modulators of macrophage training and SARS-CoV-2 infection.

Abstract

Biologically active small molecules can impart modulatory effects, in some cases, providing extended long-term memory. In a screen of biologically active small molecules for regulators of TNF induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing LPS-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits β-glucan-induced H3K4Me3 marks at the promoters of several proinflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for β-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of SARS CoV-2 and OC43 coronavirus infection, highlighting a potential application of this molecule and other Syk kinase inhibitors as prophylactic treatments for viral susceptibility.