Angiotensin Converting Enzyme 2 is a molecular decoy for targeted photodynamic SARS-CoV-2 inactivation.

The Angiotensin Converting Enzyme 2 (ACE2) is the obligate receptor for the entry of SARS-CoV-2 into host cells, through high affinity interaction with the viral protein Spike. In this work, ACE2 is exploited to devise a supramolecular construct, able to deliver photoactive molecules to the viral surface. Using a modular approach, we propose a self-assembled photoactive supramolecular structure, where a biotinylated recombinant soluble human ACE2 (rshACE2) acts as a molecular decoy, to detract the viral particles from binding to the host cell receptors. The photoactive unit of the compound is streptavidin, functionalized with either a fluorophore or a photosensitizer, that spontaneously binds biotinylated rshACE2. Using STimulated Emission Depletion (STED) microscopy, direct STochastic Optical Reconstruction Microscopy (dSTORM), and Fluorescence Correlation Spectroscopy (FCS) we demonstrate binding of the supramolecular construct to the viral particles. We show that the presence of a photosensitizing unit in the assembly warrants photoinactivation of SARS-CoV-2. A > 1000-fold reduction in viral titer is observed, when the viral suspension is exposed to the supramolecular construct (100 nM, light fluence 20 J/cm). Importantly, inactivation is observed also in the dark (>1000-fold reduction of viral titer at 300 nM), through inhibition of binding of viral particles to the host cell receptors. TABLE OF CONTENTS ENTRY: The Angiotensin Converting Enzyme 2 acts as a molecular decoy able to deliver photoactive compounds for photodynamic inactivation of SARS-CoV-2.