UC Irvine

Abstract The interaction between the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S1) and human ACE2 receptor is essential for viral entry into host epithelial cells and a key target for drug discovery. Here, we describe the evolution of a threomer, a base-modified version of threose nucleic acid (TNA), that binds to the S1 protein and inhibits its interaction with ACE2. The aptamer was isolated by in vitro selection using a DNA display strategy that linked each TNA molecule to its encoding double-stranded DNA template. Following iterative cycles of selection and amplification, lead candidates were identified by parallelized screening of individual variants in hydrogel particles. The top-performing hit exhibits low nanomolar affinity to the S1 protein and inhibits formation of the S1−ACE2 complex. Together, this work establishes threomers as an emerging platform for inhibiting protein−protein interactions in therapeutic targets.