Omicron is fading, but no one knows when the pandemic will finally end, and when and where the next coronavirus will outbreak. Therefore, it is still necessary to develop SARS-CoV-2 inhibitors, for various variants or new coronavirus. Since SARS-CoV-2 uses its surface spike glycoprotein (S protein) to recognize human receptor ACE2 (hACE2), mediating its entry into cells, ligands which can specifically recognize S protein have the potential to prevent the infection. Our lab has recently discovered DNA aptamers against the S2 domain of wild-type S protein using DNA SELEX. After optimization, among all candidates aptamer S2A2C1 has the shortest sequence, and also has the best binding affinity towards S2 protein. More importantly, as an aptamer which does not bind to the receptor binding domain (RBD) of S protein, S2A2C1 showed the virtuous efficacy to block S protein/hACE2 interaction, suggesting an RBD independent approach. To further improve its efficacy, we conjugated S2A2C1 with a reported anti-RBD aptamer, S1B6C3, using suitable linkers to construct fusion aptamers. The optimized S1B6C3-A5-S2A2C1, among all candidates, showed the best binding affinity and inhibition efficacy against S protein. Both S2A2C1 and S1B6C3-A5-S2A2C1 maintain high inhibition efficacy to prevent Delta or Omicron S protein binding to hACE2, making them well-suited as diagnostic and therapeutic molecular tools to SARS-CoV-2 and its variants. Our approach to discover aptamer inhibitors targeting the relatively conserved S2 domain, as well as the strategy to design fusion aptamers, can also be used to target any new coronaviruses as they emerge in the future.

DNA aptamers inhibit SARS-CoV-2 spike protein binding to hACE2 by an RBD-independent or dependent approach

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ACS Fall 2022

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