Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects
Sirle Saul, … , Aarthi Narayanan, Shirit Einav
Sirle Saul, … , Aarthi Narayanan, Shirit Einav
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(19):e169510. https://doi.org/10.1172/JCI169510.
View: Text | PDF
Research Article Virology Article has an altmetric score of 5

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

Abstract

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2–induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

Authors

Sirle Saul, Marwah Karim, Luca Ghita, Pei-Tzu Huang, Winston Chiu, Verónica Durán, Chieh-Wen Lo, Sathish Kumar, Nishank Bhalla, Pieter Leyssen, Farhang Alem, Niloufar A. Boghdeh, Do H.N. Tran, Courtney A. Cohen, Jacquelyn A. Brown, Kathleen E. Huie, Courtney Tindle, Mamdouh Sibai, Chengjin Ye, Ahmed Magdy Khalil, Kevin Chiem, Luis Martinez-Sobrido, John M. Dye, Benjamin A. Pinsky, Pradipta Ghosh, Soumita Das, David E. Solow-Cordero, Jing Jin, John P. Wikswo, Dirk Jochmans, Johan Neyts, Steven De Jonghe, Aarthi Narayanan, Shirit Einav

×

Figure 3

Lapatinib is a potent broad-spectrum antiviral with a high genetic barrier to resistance and is protective in human gNVU and murine models of VEEV.

Options: View larger image (or click on image) Download as PowerPoint
Lapatinib is a potent broad-spectrum antiviral with a high genetic barri...
(A) Schematic of the experiment shown in B. (B) Dose response to lapatinib of infection with vaccine (TC-83) and WT (TrD) VEEV strains (MOI = 0.1) in U-87 MG cells via plaque and alamarBlue assays at 24 hpi, respectively. (C) VEEV (TC-83) was used to infect U-87 MG cells (MOI = 0.1) and then passaged every 24 hours by inoculation of naive cells with equal volumes of supernatants under DMSO treatment or selection with lapatinib or ML336 increasing from 2.5 to 15 μM over 10 passages. Viral titers were measured by plaque assays. (D and E) Dose response to lapatinib (D) and ML336 (E) of VEEV (TC-83) harvested after 10 passages in the presence of lapatinib (D) and ML336 (E) via luciferase assays. (F) Schematic of gNVU. (G and H) Viral load in longitudinal samples collected from the vascular (G) and brain (H) sides of the gNVU after infection with VEEV (TrD) and treatment with lapatinib or DMSO. (I–L) Weight loss (I and K) and mortality (J and L) of VEEV (TC-83)–infected C3H/HeN mice treated once (I and J) or twice (K and L) daily for 14 (I and J) or 10 (K and L) days with vehicle or lapatinib (200 mg/kg) (n = 2–5 per group). (M and N) Viral titers in brain (M) and serum (N) samples obtained upon euthanasia for morbidity or at the end of the experiment from mice treated twice daily (n = 2–5 per group). In N, day 8 (vehicle) and day 10 (lapatinib) titers were compared. Data in B, D, and E are relative to DMSO. Data are representative (C, D, E, G, and H) or a combination (B) of 2 independent experiments with 2–3 replicates each. See another independent experiment associated with G and H in Supplemental Figure 4E. Means ± SD are shown. QD, once daily; BID, twice daily; UI, uninfected.