(6d) Antibody-Recruiting Protein-Catalyzed Capture Agents As a Rapid Therapeutic Countermeasure Against the Novel Coronavirus Sars-Cov-2

The novel coronavirus (SARS-CoV-2) emerged in late 2019 in Wuhan, China, and quickly spread worldwide, infecting millions and causing a high death toll alongside devastating economic damage. A gap in our ability to address the SARS-CoV-2 outbreak is the lack of an effective therapy. Here, we apply a versatile all-synthetic platform, called the antibody-recruiting protein-catalyzed capture agents (AR-PCCs), to rapidly generate highly targeted anti-viral compounds against SARS-CoV-2. AR-PCCs are composed of two molecular motifs: an epitope-specific peptide macrocycle (the PCC) that binds the pathogen, and a hapten (the AR moiety) that recruits endogenous antibodies. We hypothesized that AR-PCCs that adsorb to functional regions of SARS-CoV-2 would recruit antibodies that disable viral function and promote immune clearance. Bioinformatics, structural, and molecular dynamics analyses prioritized several target epitopes on the SARS-CoV-2 spike protein, which mediates cellular entry of the SARS-CoV-2 virion. Subsequent PCC screens against these epitopes yielded cohorts of consensus peptide ligands with high sequence homology, which were then vetted for high-affinity binding to full-length spike in high-throughput Luminex and ELISA platforms. Lead PCC binders were subjected to medicinal-chemistry type modifications to provide molecular-level insights into binding avidity, as well as to enhance in vivo performance metrics. The most promising PCCs were conjugated with an antibody-recruiting hapten, 2,4-dinitrophenyl, and interrogated by viral neutralization assays using live virus. In vivo testing of AR-PCCs in SARS-CoV-2 animal models is on-going. The work here demonstrates that AR-PCCs can be developed on an accelerated timescale of a few months, making the technology capable to address rapid pandemic outbreaks such as SARS-CoV-2.