Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

Abstract

Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of imatinib in multiple models. Our results indicated that imatinib and another TKI, the masitinib, exhibit an antiviral activity in VeroE6 cells. However, imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of imatinib and similar TKIs as antivirals in the treatment of Covid-19.

Keywords: Antivirals; Coronavirus; Covid-19; Imatinib; SARS-CoV-2; Tyrosine kinase inhibitor.

Fig. 1

Antiviral activity of different tyrosine Kinase inhibitors in VeroE6 cells. Dose response curve and cell viability for imatinib (A), masitinib (B) and asciminib (C) and control compound remdesivir (D). E: Table of EC50, EC90, CC50 and SI of the different tyrosine kinase inhibitors. Results presented in the table for Imatinib and remdesivir are the mean ± SD from three independent experiments.

Fig. 2

Antiviral activity of imatinib in a bronchial human airway epithelium Graphical representation of the experiment (A). Kinetics of virus excretion at the apical side of the epithelium measured using an RT-qPCR assay (B) and a TCID₅₀ assay (C). Data represent mean ± SD of three independents experiments, each performed in duplicate (n = 6). Statistical significance was calculated by Kruskal-Wallis ANOVA versus untreated group. Rem (Remdesivir at 10 μM) was used as a positive drug control.*, ** and *** symbols indicate that the average value for the group is significantly lower than that of the untreated group with a p-value ranging between 0.01 and 0.05, 0.001–0.01 and 0.0001–0.001 respectively. The graphical representation was created with BioRENDER.com.

Fig. 3

Antiviral activity of imatinib in a Golden Syrian hamster model. A: Experimental timeline of antiviral activity assessment at day 3 and lung histopathological examination at day 5. Groups of 4 or 6 hamsters were intranasally infected with 10⁴ TCID₅₀ of SARS-CoV-2 and received the imatinib, orally twice a day. Favipiravir was used as a positive control. B: Lung infectious titers (measured using a TCID₅₀ assay) expressed in TCID₅₀/g of lung. C: Viral RNA yields (measured using an RT-qPCR assay) expressed in viral genome copies/g of lung. D: Scoring of lung pathological changes with or without different expositions to imatinib. Based on mutliple criteria: severity of inflammation, alveolar hemorrhagic necrosis and vessel lesions, a cumulative score from 0 to 10 was estimated and assigned to a grade of severity (I, II, III and IV) as previously described (Driouich et al., 2021) imatinib 32 mg/day¹ and imatinib 32 mg/day² are results from two independent experiments. Data represent mean ± SD. **, ***symbols indicate that the average value for the group is significantly lower than that of the untreated group with a p-value ranging 0.001–0.01 and 0.0001–0.001 respectively. The experimental timeline was created with BioRENDER.com.