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, the 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 (the atypical antipsychotic Ziprasidone, the antihistamine Buclizine, the antiviral Beclabuvir and the antimalaric Artefenomel) as capable of  lowering ACE2 expression in Vero cells in a dose-dependent fashion. Importantly, these molecules potently inhibited the entry into cells of a pseudotyped retrovirus exposing the SARS-CoV-2 spike protein. Our results indicate that these drugs could act against SARS-CoV-2 by altering the folding pathway of its receptor ACE2. Ongoing studies are directly evaluating the possibility of repurposing these drugs for the treatment of COVID-19 .
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 (the atypical antipsychotic Ziprasidone, the antihistamine Buclizine, the antiviral Beclabuvir and the antimalaric Artefenomel) as capable of dose-dependently lowering ACE2 expression in Vero cells . These molecules 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 a promising antiviral activity against SARS-CoV-2 .
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by altering the folding pathway of its receptor ACE2. Ongoing studies are directly evaluating the possibility of repurposing these drugs for the treatment of COVID-19
(MEX-BC2/2020 strain). One of the selected drugs (Artefenomel) could completely prevent cytopathic effects induced by the presence of the virus, thus showing a promising antiviral activity against SARS-CoV-2