Avidity by Design: Scalable Programmed Synthesis of Bivalent DNA-Encoded Libraries for Enhanced Selection Sensitivity
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Institution: insitro, inc. (United States)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7204942595