Broadly neutralizing aptamers to SARS-CoV-2: A diverse panel of modified DNA antiviral agents

Since its discovery, COVID-19 has rapidly spread across the globe and has had a massive toll on human health, with infection mortality rates as high as 10%, and a crippling impact on the world economy. Despite numerous advances, there remains an urgent need for accurate and rapid point-of-care diagnostic tests and better therapeutic treatment options. To contribute chemically distinct, non-protein-based affinity reagents, we report here the identification of modified DNA-based aptamers that selectively bind to the S1, S2, or receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Several aptamers inhibit the binding of the spike protein to its cell-surface receptor angiotensin-converting enzyme 2 (ACE2) and neutralize authentic SARS-CoV-2 virus in vitro, including all variants of concern. With a high degree of nuclease resistance imparted by the base modifications, these reagents represent a new class of molecules with potential for further development as diagnostics or therapeutics. [Display omitted] We report a generally applicable method for developing modified DNA aptamer antagonists to viral targets, in this case, the SARS-CoV-2 spike protein. We identified an antiviral agent with potent activity against all variants of concern of SARS-CoV-2. Broad neutralization activity is due to occupancy of a conserved epitope overlapping the receptor-binding motif.