Issue 46, 2024

A potent and selective anti-glutathione peroxidase 4 nanobody as a ferroptosis inducer

Abstract

Glutathione peroxidase 4 (GPX4) plays a crucial role in the ferroptosis pathway, emerging as a potential drug target in the treatment of refractory tumors. Unfortunately, the development of GPX4-targeted treatment has been very limited due to the poor selectivity and drug-like properties of current GPX4 inhibitors. Here, we report a proof-of-concept study of potent anti-GPX4 nanobodies, successfully identified through immunizing Bactrian camels and constructing a phage library. Utilizing a cell-penetrating peptide fusion strategy, these nanobodies with high affinities to GPX4 efficiently internalized in cells and formed the basis for further applications. In particular, 12E significantly inhibited cellular GPX4 and consequently induced remarkable ferroptosis in cancer cells. Furthermore, 12E could impair zebrafish dorsal organizer formation in vivo, as evidenced by a phenotype comparable to that observed in zebrafish with the gpx4b gene knocked out. The new GPX4-inhibiting nanobody described here exhibits superior proteome-wide selectivity and a vastly improved safety profile compared to existing GPX4 inhibitors. These incredible features of 12E, as an anti-GPX4 nanobody, may not only contribute to ferroptosis-related anticancer treatment but also establish a new paradigm for nanobodies in drug development for traditionally undruggable targets.

Graphical abstract: A potent and selective anti-glutathione peroxidase 4 nanobody as a ferroptosis inducer

Supplementary files

Article information

Article type
Edge Article
Submitted
14 Aug 2024
Accepted
14 Oct 2024
First published
29 Oct 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 19420-19431

A potent and selective anti-glutathione peroxidase 4 nanobody as a ferroptosis inducer

X. Li, Y. Li, A. Xie, F. Chen, J. Wang, J. Zhou, X. Xu, Z. Xu, Y. Wang and X. Qiu, Chem. Sci., 2024, 15, 19420 DOI: 10.1039/D4SC05448B

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