CiD agonists: Circular DNA-based agonists for the fine-tuning of receptor signaling

16 June 2022, Version 1

Abstract

Receptor dimerization geometry plays a significant role in signal transduction induced by growth factors and cytokines. A chemical strategy capable of controlling dimerization geometry provides a means for studying receptor activation mechanisms and designing novel agonists transducing fine-tuned receptor signaling. However, a generalized approach that can be applied to given receptors is still limited. In the present study, we propose a strategy using CiD agonists (circular DNA aptamer-based agonists), where circularized DNA is used as a rigid scaffold to present two receptor-binding aptamers from the duplex linker domain in a fixed distance and orientation. We targeted Met, a receptor for hepatocyte growth factor (HGF), and designed Met-binding CiD agonists with variable linker length. The designed CiD agonists demonstrated a distinctive periodic change in the receptor activation potential dependent on their linker length. This strategy represents a useful approach for the rational design of partial agonists that transduce fine-tuned receptor signaling and exert moderate biological activity.

Content

Supplementary materials

Supporting Information
Supporting figures, Sequence data, and Methods
Supplementary Video
DU145 migration assay

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