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The steep climbing of victims caused by the new coronavirus disease 2019(COVID-19) throughout the planet is sparking an unprecedented effort toidentify effective therapeutic regimens to tackle the pandemic. The SARS-CoV-2virus is known to gain entry into various cell types through the binding of oneof its surface proteins (spike) to the host Angiotensin-Converting Enzyme 2(ACE2). Thus, spike-ACE2 interaction represents a major target for vaccines andantiviral drugs. A novel method has been recently described by some of theauthors to pharmacologically downregulate the expression of target proteins atthe post-translational level. This technology builds on computationaladvancements in the simulation of folding mechanisms to rationally blockprotein expression by targeting folding intermediates, hence hampering thefolding process. Here, we report the all-atom simulations of the entiresequence of events underlying the folding pathway of ACE2. Our data revealedthe existence of a folding intermediate showing two druggable pockets hidden inthe native conformation. Both pockets were targeted by a virtual screeningrepurposing campaign aimed at quickly identifying drugs capable to decrease theexpression of ACE2. We identified four compounds capable of lowering ACE2expression in Vero cells in a dose-dependent fashion. All these molecules werefound to inhibit the entry into cells of a pseudotyped retrovirus exposing theSARS-CoV-2 spike protein. Importantly, the antiviral activity has been testedagainst live SARS-CoV-2 (MEX-BC2/2020 strain). One of the selected drugs(Artefenomel) could completely prevent cytopathic effects induced by thepresence of the virus, thus showing antiviral activity against SARS-CoV-2.Ongoing studies are further evaluating the possibility of repurposing thesedrugs for the treatment of COVID-19.

Antimalarial Artefenomel Inhibits Human SARS-CoV-2 Replication in Cells while Suppressing the Receptor ACE2