Abstract
The causative agent of COVID-19, SARS-CoV-2, gains access to cells through interactions of the receptor-binding domain (RBD) on the viral S protein with angiotensin-converting enzyme 2 (ACE2) on the surface of human host cells. Systematic evolution of ligands by exponential enrichment (SELEX) was used to generate aptamers (nucleic acids selected for high binding affinity to a target) to the RBD made from 2ʹ-fluoro-arabinonucleic acid (FANA). The best selected ~79 nucleotide aptamers bound the RBD (Arg319-Phe541) and the larger S1 domain (Val16-Arg685) of the 1272 amino acid S protein with equilibrium dissociation constants (KD,app) of ~10–20 nM, and binding half-life for the RBD, S1 domain, and full trimeric S protein of 53 ± 18, 76 ± 5, and 127 ± 7 min, respectively. Aptamers inhibited the binding of the RBD to ACE2 in an ELISA assay. Inhibition, on a per weight basis, was similar to neutralizing antibodies that were specific for RBD. Aptamers demonstrated high specificity, binding with about 10-fold lower affinity to the related S1 domain from the original SARS virus, which also binds to ACE2. Overall, FANA aptamers show affinities comparable to previous DNA aptamers to RBD and S1 protein and directly block receptor interactions while using an alternative Xeno-nucleic acid (XNA) platform.
Highlights
The coronavirus SARS-CoV-2 has had a devastating impact on society that will likely continue into the foreseeable future
We describe the selection of aptamers, which are short nucleic acidbased sequences that bind with high affinity to targets, to block the interaction between the S protein and the angiotensin-converting enzyme 2 (ACE2) receptor
We describe the generation of fluoro-arabinonucleic acid (FANA) aptamers to the receptor-binding domain (RBD) of the SARS-CoV-2 S protein that can block the interactions between the S protein and ACE2 receptor
Summary
The coronavirus SARS-CoV-2 has had a devastating impact on society that will likely continue into the foreseeable future. Infection with SARS-CoV-2 requires interaction between the viral surface protein, spike (S), and a host “receptor” protein, angiotensinconverting enzyme 2 (ACE2) [3], that is expressed on type II alveolar cells [4] and ciliated cells in the human airway epithelium (HAE) [5], making these cells potentially vulnerable to infection. Antibodies that block this interaction have been successfully used to mitigate. Aptamers have shown potent antiviral activity and low toxicity in cell culture [14,19,20,21,22,23,24,25,26,27,28,29], and they are among the most potent inhibitors of protein activity in vitro [30,31,32]
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