Avidity by Design: Scalable Programmed Synthesis of Bivalent DNA-Encoded Libraries for Enhanced Selection Sensitivity
Abstract
DNA Encoded Libraries (DELs) are used for finding small molecule binders to proteins and other targets of pharmaceutical interest. DELs tether small molecules made by combinatorial chemistry to DNA oligos whose sequences identify the molecules to which they are tethered. DEL selections, or screens, typically separate binders from non-binders and use sequencing to discern binder structures. Typically, selection methods more efficiently capture tighter binders than weaker ones. There are two key reasons why DEL selections may return very few, or no binders. One is the presence of only a few binders in the library (or none); less appreciated is the case where there are true binders, but the selection protocol lacks the sensitivity to capture them. We report in our “Theoretical Analysis of Bivalent Binding Avidity and Kinetics: Implications for DNA-Encoded Libraries” that through an avidity effect bivalent DELs increase the sensitivity of selections and capture more and weaker binders than their cognate monovalent counterparts. Here, we present our development of the means to efficiently build bivalent DELs.
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BibTeX
@misc{akki2026avidity,
title = {{Avidity by Design: Scalable Programmed Synthesis of Bivalent DNA-Encoded Libraries for Enhanced Selection Sensitivity}},
author = {Spurti U Akki and Yasmin Arjomandi and Tracy Chan and Kirill Novikov and Divya Kanichar and Patrick J McEnaney and Vincent Lee and Jacob H Pachter and Joshua L Turnbull and Nikhil Jain and Virja A Pandya and Nathaniel H Stanley and Dong Min Mun and Christoph Klein and Boris P Belotserkovskii and R. Edward Watts},
howpublished = {ChemRxiv},
year = {2026},
month = aug,
doi = {10.26434/chemrxiv.15008128/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008128/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Avidity by Design: Scalable Programmed Synthesis of Bivalent DNA-Encoded Libraries for Enhanced Selection Sensitivity
AU - Spurti U Akki
AU - Yasmin Arjomandi
AU - Tracy Chan
AU - Kirill Novikov
AU - Divya Kanichar
AU - Patrick J McEnaney
AU - Vincent Lee
AU - Jacob H Pachter
AU - Joshua L Turnbull
AU - Nikhil Jain
AU - Virja A Pandya
AU - Nathaniel H Stanley
AU - Dong Min Mun
AU - Christoph Klein
AU - Boris P Belotserkovskii
AU - R. Edward Watts
PY - 2026
DA - 2026/08/31
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008128/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008128/v1
AB - DNA Encoded Libraries (DELs) are used for finding small molecule binders to proteins and other targets of pharmaceutical interest. DELs tether small molecules made by combinatorial chemistry to DNA oligos whose sequences identify the molecules to which they are tethered. DEL selections, or screens, typically separate binders from non-binders and use sequencing to discern binder structures. Typically, selection methods more efficiently capture tighter binders than weaker ones. There are two key reasons why DEL selections may return very few, or no binders. One is the presence of only a few binders in the library (or none); less appreciated is the case where there are true binders, but the selection protocol lacks the sensitivity to capture them. We report in our “Theoretical Analysis of Bivalent Binding Avidity and Kinetics: Implications for DNA-Encoded Libraries” that through an avidity effect bivalent DELs increase the sensitivity of selections and capture more and weaker binders than their cognate monovalent counterparts. Here, we present our development of the means to efficiently build bivalent DELs.
ER -