Saracatinib Inhibits Middle East Respiratory Syndrome-Coronavirus Replication In Vitro

Abstract

The Middle East respiratory syndrome-coronavirus (MERS-CoV), first identified in Saudi Arabia, is an emerging zoonotic pathogen that causes severe acute respiratory illness in humans with a high fatality rate. Since its emergence, MERS-CoV continues to spread to countries outside of the Arabian Peninsula and gives rise to sporadic human infections following the entry of infected individuals to other countries, which can precipitate outbreaks similar to the one that occurred in South Korea in 2015. Current therapeutics against MERS-CoV infection have primarily been adapted from previous drugs used for the treatment of severe acute respiratory syndrome. In search of new potential drug candidates, we screened a library composed of 2334 clinically approved drugs and pharmacologically active compounds. The drug saracatinib, a potent inhibitor of Src-family of tyrosine kinases (SFK), was identified as an inhibitor of MERS-CoV replication in vitro. Our results suggest that saracatinib potently inhibits MERS-CoV at the early stages of the viral life cycle in Huh-7 cells, possibly through the suppression of SFK signaling pathways. Furthermore, saracatinib exhibited a synergistic effect with gemcitabine, an anticancer drug with antiviral activity against several RNA viruses. These data indicate that saracatinib alone or in combination with gemcitabine can provide a new therapeutic option for the treatment of MERS-CoV infection.

A Systematic Review of therapeutic agents for the treatment of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

“…Moreover, the combination of INF-α2b and ribavirin in Vero cells showed augmentation of action and facilitates the reduction of the doses of IFN-α2b and ribavirin to lower concentrations suggesting possible utility in clinical use [30]. Saracatinib with Gemcitabine had no difference in cytotoxicity compared with Saracatinib alone but was less cytotoxic compared with gemcitabine alone [44]. There were many drugs that were used in vitro and showed effectiveness, however, translating the findings from these studies into clinical trial remains of particular importance especially taking into consideration availability, pharmacokinetic properties, pharmacodynamic characteristics and possible side effects [69].…”

“…Saracatinib has a broad-spectrum antiviral activity against different strain of MERS-CoV. After 72 h of infection of Huh-7 cells, Saracatinib exhibited an EC50 of 2.9 μM and CC50 of more than 50 μM [44]. Whereas, gemcitabine was shown to be effective against MERS-CoV infected Huh-7 cells with an EC50 of 1.2 μM and a complete viral depletion at a dose of ≥1 μM [44].…”

“…After 72 h of infection of Huh-7 cells, Saracatinib exhibited an EC50 of 2.9 μM and CC50 of more than 50 μM [44]. Whereas, gemcitabine was shown to be effective against MERS-CoV infected Huh-7 cells with an EC50 of 1.2 μM and a complete viral depletion at a dose of ≥1 μM [44]. Inhibitory effect of resveratrol against MERS-CoV was tested using infected Vero E6 cells.…”

Recent discovery and development of inhibitors targeting coronaviruses

“…Current anti-MERS-CoV agents have been primarily resulted from previous drugs used for the SARS-CoV infection. To identify potential antiviral agents against MERS-CoV, Shin et al screened a library consisting of 2334 approved drugs and pharmaceutically active compounds [76]. This yielded a series of hit compounds, primarily categorized as anti-protozoal, anti-cancer, anti-psychotics (11-18, Fig.…”

“…The co-crystal structures of SARS-CoV 3CL pro with decahydroisoquinoline inhibitors (76)(77)(78)(79)(80) revealed that P2-decahydroisoquinoline scaffold was inserted into a large S2 pocket and the P1-imidazole was occupied into the S1 pocket as Structure of 3CL pro inhibitors that contain Michael acceptor, aldehyde and activated carbonyl functional groups.…”