Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent

The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research 2020, 178, 104787) show a potent inhibition of SARS-CoV-2 replication in vitro by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL^pro and PL^pro, and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host- and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.