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Herein, click\u2010systematic evolution of ligands by exponential enrichment (SELEX) is employed to generate chemically modified DNA aptamers, termed clickmers, that target the SARS\u2010CoV\u20102 spike (CoV2\u2010S) glycoprotein. Two independent split\u2010combine selection strategies yield distinct clickmer families functionalized with benzofuran or indole moieties. Lead candidates (BF1 and N2) demonstrate nanomolar affinity for wild\u2010type CoV2\u2010S and maintain binding to multiple variants, including Alpha, Delta, and Mu, as validated by flow cytometry, surface plasmon resonance, and microscale thermophoresis. Structure\u2013function analysis reveals essential click\u2010in positions for both full\u2010length clickmers and a truncated N2 variant, as short as 31 nucleotides, which displays increased binding to the Omicron variant. These results highlight the versatility of the click\u2010SELEX platform and exemplify its successful application to a clinically relevant target, advancing previous developments in the field.<\/jats:p>","DOI":"10.1002\/cbic.202500733","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T07:50:49Z","timestamp":1768031449000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selection and Characterization of SARS\u2010CoV\u20102 Spike Binding Clickmers"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2484-0621","authenticated-orcid":false,"given":"Nima","family":"Moradzadeh","sequence":"first","affiliation":[{"name":"Life &amp; Medical Sciences (LIMES) Institut Chemical Biology &amp; Medicinal Chemistry Unit Universit\u00e4t Bonn  Gerhard\u2010Domagk\u2010Str. 1 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6047-6785","authenticated-orcid":false,"given":"Anna","family":"Jonczyk","sequence":"additional","affiliation":[{"name":"Life &amp; 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