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Photoactivatable Plant Hormone-Based Chemical Inducers of Proximity for In Vivo Applications

Authors: Philipp Pöschko,Caroline M. Berrou,Kaisa Pakari,Michael J. Ziegler,Christoph Kern,Birgit Koch,Joachim Wittbrodt,Richard Wombacher
Publisher: American Chemical Society (ACS)
Publish date: 2025-1-27
ISSN: 1554-8929,1554-8937 DOI: 10.1021/acschembio.4c00592
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Could the authors clarify why pOP induces protein proximity without irradiation in live medaka embryos (Figure 3C), while it remains inactive in mammalian cells without light exposure? Could this be due to enzymatic cleavage or other in vivo factors?

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1 week, 2 days ago

In mammalian cells, pOP maintains its photocaged state in the absence of light, with minimal background activity confirmed via luciferase transcription assays and colocalization studies. However, in live medaka embryos, protein proximity was induced without irradiation following the administration of pOP. The authors hypothesize that this is due to non-photolytic cleavage of the ester bond connecting the photocage to the active CIP molecule—likely catalyzed by endogenous esterases or other enzymatic processes inherent to the medaka embryonic environment.

This unintended decaging is not observed with pMandi, which features a photocage bound to an amide nitrogen, conferring significantly greater resistance to hydrolytic cleavage compared to the ester linkage in pOP. The differential chemical stability of these photocaging strategies likely explains the observed disparity in light-independent activation between pOP and pMandi across different biological systems.

Hence, the background activation of pOP in medaka is not due to intrinsic activity of the CIP itself, but rather to enzymatic cleavage in vivo, a limitation that the authors acknowledge and aim to address in future iterations through the development of more hydrolytically stable photocaged derivatives.

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