Automated DNA-Encoded Library Synthesis on Magnetic Anion Exchange Resin
Abstract
DNA-encoded libraries (DELs) access vast chemical spaces for drug discovery, but split-and-pool DEL synthesis remains the sole and very manual portion of the DEL workflow. Here, we automate DEL construction using diethylaminoethyl-functionalized weak anion exchange (WAX) magnetic resin and a KingFisher Apex particle-handling instrument. DNA encoding occurs in solution, followed by selective immobilization of DNA conjugates under low-salt conditions that exclude > 95% of unused encoding oligonucleotides. On-DNA chemistry then proceeds using the WAX resin-adsorbed "WAX-ON" DNA substrate in neat organic solvent. The platform supports amide formation, reductive amination, copper-catalyzed azide-alkyne cycloaddition, and Fmoc removal. Automated bead transfer enables iterative reaction and washing cycles. We synthesized two-cycle 9,216-member DELs from 96 Fmoc-protected amino acids and 96 carboxylic acids. Control selections reproducibly enriched the carbonic anhydrase ligand sulfamoylbenzoic acid. Magnetic WAX-ON DEL synthesis is compatible with diverse chemistries and uses the same instrumentation to automate end-to-end DEL preparation and affinity screening.
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BibTeX
@misc{cavett2026automated,
title = {{Automated DNA-Encoded Library Synthesis on Magnetic Anion Exchange Resin}},
author = {Valerie Cavett and Santino L. DeGirolamo and Erika M. Cerna Arroyo and Robert Damoiseaux and Brian M. Paegel},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760614},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760614v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Automated DNA-Encoded Library Synthesis on Magnetic Anion Exchange Resin
AU - Valerie Cavett
AU - Santino L. DeGirolamo
AU - Erika M. Cerna Arroyo
AU - Robert Damoiseaux
AU - Brian M. Paegel
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760614
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760614v1
AB - DNA-encoded libraries (DELs) access vast chemical spaces for drug discovery, but split-and-pool DEL synthesis remains the sole and very manual portion of the DEL workflow. Here, we automate DEL construction using diethylaminoethyl-functionalized weak anion exchange (WAX) magnetic resin and a KingFisher Apex particle-handling instrument. DNA encoding occurs in solution, followed by selective immobilization of DNA conjugates under low-salt conditions that exclude > 95% of unused encoding oligonucleotides. On-DNA chemistry then proceeds using the WAX resin-adsorbed "WAX-ON" DNA substrate in neat organic solvent. The platform supports amide formation, reductive amination, copper-catalyzed azide-alkyne cycloaddition, and Fmoc removal. Automated bead transfer enables iterative reaction and washing cycles. We synthesized two-cycle 9,216-member DELs from 96 Fmoc-protected amino acids and 96 carboxylic acids. Control selections reproducibly enriched the carbonic anhydrase ligand sulfamoylbenzoic acid. Magnetic WAX-ON DEL synthesis is compatible with diverse chemistries and uses the same instrumentation to automate end-to-end DEL preparation and affinity screening.
SN - 2692-8205
ER -