Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects

Abstract

Effective therapies are needed to combat emerging viruses. Seventeen candidates that rescue cells from SARS-CoV-2-induced lethality and target diverse functions emerged in a screen of 4,413 compounds. Among the hits was lapatinib, an approved inhibitor of the ErbB family of receptor tyrosine kinases. Lapatinib and other pan-ErbB inhibitors suppress replication of SARS-CoV-2 and unrelated viruses with a high barrier to resistance. ErbB4, but not lapatinib's cancer targets ErbB1 and ErbB2, is required for SARS-CoV-2 entry and Venezuelan equine encephalitis virus infection and is a molecular target mediating lapatinib's antiviral effect. In human lung organoids, lapatinib protects from SARS-CoV-2-induced activation of pathways implicated in acute and chronic lung injury downstream of ErbBs (p38-MAPK, MEK/ERK, and AKT/mTOR), pro-inflammatory cytokine production, and epithelial barrier injury. These findings reveal regulation of viral infection, inflammation, and tissue injury via ErbBs and propose approved candidates to counteract these effects with implications for coronaviruses and unrelated viruses.

Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for therapy

“…Beyond viral entry, the time-of-addition experiments provide evidence that NAKs are also involved in regulating later stage(s) of the viral life cycle, likely assembly and/or egress, but not viral RNA replication. This is in agreement with our prior findings involving their roles in unrelated RNA viral infections such as DENV, EBOV, and VEEV (Neveu et al, 2015; Bekerman et al, 2017; Pu et al, 2020; Saul et al, 2020; Huang et al, 2021; Saul et al, 2021; Saul et al, 2021). Together, these findings provide evidence that NAKs regulate temporally distinct stages of the SARS-CoV-2 life cycle and represent candidate targets for anti-SARS-CoV-2 treatment.…”

“…Since RMC-76 demonstrated an effect on viral entry and SARS-CoV-2 is thought to enter target cells in part via CME (Bayati et al, 2021; Koch et al, 2021), we tested the hypothesis that NAKs are involved in mediating SARS-CoV-2 entry. To this end, we first used vesicular stomatitis virus encapsidated RNA pseudotyped with the SARS-CoV-2 spike glycoprotein expressing a luciferase reporter gene (rVSV-SARS-CoV-2-S) (Khanna et al, 2020; Saul et al, 2021). Calu-3 cells depleted of the individual NAKs ( Figure 1B ) were infected with rVSV-SARS-CoV-2-S followed by luciferase assays at 24 hpi ( Figure 6A ).…”

Competing endogenous RNA network mediated by circ_3205 in SARS-CoV-2 infected cells

“…Some members of HSP90 family have been recently suggested to foster MERS-CoV, SARS-CoV and SARS-CoV-2 replication and proinflammatory cytokine expression [ 90 , 91 ]. Subnetworks generated by the study of centralities further revealed an enrichment in BPs strictly related to the local and systemic effects of SARS-CoV-2 infection, such as remodeling of protein trafficking within infected host cell [ 92 ], mucus hypersecretion [ 93 ], ErbB protein family and growth factor receptor signaling [ 94 , 95 ], and unfolded protein response [ 96 ]. Collectively, these findings corroborate our hypothesis of a functional involvement of KCNMB4 and PRKCE in SARS-CoV-2 infection.…”

Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies

“…As described in ( Saul et al, 2021b ), HEK-293T cells were transfected with 30 μg of a Spike expression plasmid. After 24 h, the medium was replaced and cells were treated with valproic acid (VPA).…”