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Working with Paul Zamecnik during the late 1980s and early 1990s, I witnessed the transition from a simple steric-block model of antisense action to the recognition of RNase H as the central driver of potency. Our systematic exploration of backbone and sugar modifications revealed the limitations of single-chemistry approaches and led to the development of hybrid antisense constructs that combined deoxyribonucleotide with 2\u2032-modified ribonucleotide segments, all PS-modified. Such designs later became known as gapmers and provided enhanced stability, improved affinity, and efficient RNase H activation. Although our initial efforts with phosphorothioate oligonucleotides faltered in the clinic, continued refinement of the hybrid designs ultimately enabled the development of multiple approved drugs. Here I describe how a concept sketched on a chalkboard evolved into a widely adopted therapeutic platform.<\/jats:p>","DOI":"10.1021\/acsomega.6c06721","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:02:31Z","timestamp":1790658151000},"page":"60497-60504","source":"Crossref","is-referenced-by-count":0,"title":["From a Concept\non a Chalkboard to Gapmer Antisense"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4275-2510","authenticated-orcid":true,"given":"Sudhir","family":"Agrawal","sequence":"first","affiliation":[{"name":"Arnay Sciences , PO BOX519 , ,","place":["Shrewsbury, Massachusetts, United States, 01545"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"1","key":"2026101315103019600_cit1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1073\/pnas.75.1.285","article-title":"Inhibition of Rous sarcoma viral RNA translation by\na specific oligodeoxyribonucleotide","volume":"75","author":"Stephenson","year":"1978","journal-title":"Proc. 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