Ru(II) photocages enable precise control over enzyme activity with red light

Dmytro Havrylyuk, Austin C. Hachey, Alexander Fenton, David K. Heidary () and Edith C. Glazer ()
Additional contact information
Dmytro Havrylyuk: University of Kentucky
Austin C. Hachey: University of Kentucky
Alexander Fenton: University of Kentucky
David K. Heidary: University of Kentucky
Edith C. Glazer: University of Kentucky

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low energy (660 nm) light. These systems provide a selectivity index of 4,000–100,000 over other off-target CYPs. One key to the design was the development of coordinating CYP1B1 inhibitors, which suppress enzyme activity at pM concentrations in live cells. The metal binding group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.

Date: 2022
References: View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-31269-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31269-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-31269-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().