The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs that can help contain the outbreak. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered as a potential target for drug development. Based on in silico screening followed by in vitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor, imatinib, inhibits SARS-CoV-2 with an IC50 of 130 nM. We provide initial evidence that inhibition of virus fusion may explain the antiviral action of imatinib. This finding is significant since pinpointing the mode of action allows evaluating the drug's affinity to the SARS-CoV-2-specific target protein, and in turn, helps make inferences on the potency of the drug and evidence-based recommendations on its dosage. To this end, we provide evidence that imatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein with an affinity at micromolar, i.e., 2.32 ± 0.9 µM, levels. We also show that imatinib inhibits other coronaviruses, SARS-CoV and MERS-CoV, possibly via fusion inhibition. Based on promising in vitro results, we propose the Abl kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug candidate for further clinical validation against COVID-19.

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Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their efficacy against emerging Variants of Concern (VOCs) such as Omicron. Our research fills this gap by investigating these drugs’ impact on VOCs, a topic that current scientific literature has largely overlooked. We employed computational methodologies, including molecular mechanics and machine learning tools, to identify drugs that could potentially disrupt the SARS-CoV-2 spike RBD-ACE2 protein interaction. This led to the identification of two FDA-approved small molecule drugs, M and T, conventionally used for treating asthma and hypertension, respectively. Our study presents an additional potential use for these drugs as antivirals. Our results show that both M and T can inhibit not only the WT SARS-CoV-2 but also, in the case of M, the Omicron variant, without reaching cytotoxic concentrations. This novel finding fills an existing gap in the literature and introduces the possibility of repurposing these drugs for SARS-CoV-2 VOCs, an essential step in responding to the evolving global pandemic.