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