Issue 25, 2024

Molecular design for sub-micromolar enzyme-instructed self-assembly (EISA)

Abstract

Enzyme-instructed self-assembly (EISA) has been explored for many applications in the life sciences including imaging and therapeutics. To date, use of the strategy is limited by the relatively high concentration – often in the mM regime – required for assembly. Here, a porphyrin–peptide conjugate (1) was designed as a water-soluble, EISA substrate. Compound 1 is built around a trans-AB porphyrin chassis that is equipped with a monodisperse 1 kDa polyethylene glycol (PEG) linker (a surrogate for a potential targeting agent) and an enzymatically triggerable self-assembly motif. The latter is comprised of two identical self-assembly peptides (also known as hydrogelators) attached to the 2,6-positions of an aryl group. The peptides have sequence GffY and in protected form contain tyrosine as an O-phosphoester GffY(p). Treatment of 1 with alkaline phosphatase (ALP) gave rise to the self-assembly (or aggregation) process as characterized by absorption spectroscopy. A control compound without the phosphoester trigger was synthesized and examined for the self-assembly process using fluorescence and absorption spectroscopy. A concentration-dependent study showed that at 10 nM approximately 50% of porphyrin–peptide conjugate was in the aggregated form. The nanomolar assembly suggests possible applications of EISA substrates in chemotherapy, although a further decrease in concentration to the picomolar regime may be required for use in targeted molecular radiotherapy, where very low mass dosing is typical.

Graphical abstract: Molecular design for sub-micromolar enzyme-instructed self-assembly (EISA)

Supplementary files

Article information

Article type
Paper
Submitted
18 4 2024
Accepted
26 5 2024
First published
07 6 2024
This article is Open Access
Creative Commons BY license

New J. Chem., 2024,48, 11233-11242

Molecular design for sub-micromolar enzyme-instructed self-assembly (EISA)

Q. Liu, T. Ntim, Z. Wu, H. A. Houson, S. E. Lapi and J. S. Lindsey, New J. Chem., 2024, 48, 11233 DOI: 10.1039/D4NJ01798F

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