De novo selected hACE2 mimics that integrate hotspot peptides with aptameric scaffolds for binding tolerance of SARS-CoV-2 variants.

The frequent occurrence of viral variants is a critical problem in developing antiviral prophylaxis and therapy; along with stronger recognition of host cell receptors, the variants evade the immune system-based vaccines and neutralizing agents more easily. In this work, we focus on enhanced receptor binding of viral variants and demonstrate generation of receptor-mimicking synthetic reagents, capable of strongly interacting with viruses and their variants. The hotspot interaction of viruses with receptor-derived short peptides is maximized by aptamer-like scaffolds, the compact and stable architectures of which can be in vitro selected from a myriad of the hotspot peptide-coupled random nucleic acids. We successfully created the human angiotensin-converting enzyme 2 (hACE2) receptor-mimicking hybrid ligand that recruits the hACE2-derived receptor binding domain-interacting peptide to directly interact with a binding hotspot of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Experiencing affinity boosting by ~500% to Omicron, the de novo selected hACE2 mimic exhibited a great binding tolerance to all SARS-CoV-2 variants of concern.