Measuring the affinity of DNA-small molecule conjugates to target proteins, application to PROTACs

About the talk

Recorded at the 3rd focal Molography User Meeting on September 9, 2026. Prof. Andreas Brunschweiger (University of Würzburg) shows how focal molography measures the affinity of DNA-small molecule conjugates to their target proteins, from a PROTAC linker study on the E3 ligase VHL to the validation of hits from DNA-encoded libraries.

Topics covered

• Three questions for every conjugate. Whether a molecule sits in a DNA-encoded library or is a nucleic acid-based drug such as a DNA PROTAC, the same questions come up: how strongly does the ligand bind its target, does the linker change that binding, and is the attached oligonucleotide tolerated.
• A linker library for the E3 ligase VHL. The Brunschweiger group built a small library of VHL ligand-linker-DNA conjugates with amide bond chemistry and commercially available linkers, covering linear, peptidic, rigid and side-chain linkers. The conjugates were synthesized within one week.
• Singleplex and multiplex agree. The same library was made on one DNA tag and on 20 different DNA tags. Focal molography measured both formats with consistent values, with the multiplexed chip assay giving much higher throughput.
• Structure-activity relationship. All linkers were tolerated by VHL, the affinities agreed with literature values for the ligand alone, and more hydrophobic linkers tended to give higher affinities.
• Next step, DEL hit validation. A chemically stabilized DNA barcode allows DEL chemistry in organic solvents and a macrocycle library of close to one million compounds. Screens on FKBP proteins return far more hits than can be resynthesized one by one, which is where multiplexed affinity measurement on focal molography comes in.

About the speaker

Prof. Andreas Brunschweiger leads a research group at the University of Würzburg working on DNA-encoded chemistry, DNA-encoded libraries and nucleic acid-small molecule conjugates. The PROTAC study presented was carried out together with the lino Biotech team.

The recording is available on demand behind a short registration form.