Identification of a Druggable Intermediate along the Folding Pathway of the SARS-CoV-2 Receptor ACE2

Boldrini, Alberto; Terruzzi, Luca; Spagnolli, Giovanni; Astolfi, Andrea; Massignan, Tania; Lolli, Graziano; Barreca, Maria Letizia; Biasini, Emiliano; Faccioli, Pietro; Pieri, Lidia

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. We recently described a novel method to pharmacologically down-regulate 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 simulation of the entire sequence of events underlying the folding pathway of ACE2. Our data reveal the existence of a folding intermediate showing 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. Importantly, among the different virtual hits, we identified mefloquine, a quinoline-derivative belonging to a class of antimalaria agents (e.g. chloroquine and hydroxychloroquine) recently described for their effects on ACE2 maturation. Thus, our results suggest that these drugs could act against SARS-CoV-2 by altering the folding pathway of its receptor ACE2.