Recently, Prof. Xiaojin Zhang's team from the College of Science of our university published the latest research results entitled Light-induced, lysine-targeting irreversible covalent inhibition of the human oxygen sensing hydroxylase factor inhibiting HIF (FIH) in the international authoritative journal Journal of the American Chemical Society. Light-induced, lysine-targeting, irreversible, covalent inhibition of the human oxygen-sensing hydroxylase factor inhibiting HIF (FIH). Prof. Xiao-Jin Zhang of China Pharmaceutical University and Prof. Christopher J. Schofield of the Department of Chemistry, University of Oxford are the corresponding authors of this paper, while postdoctoral fellow Yuet Wu and PhD graduate Zhi-Hong Li of the School of Science of CUHK, PhD student Samanpreet Kaur of the University of Oxford, and MSc student Zewei Zhang (class of 2022) of the School of Science of CUHK are the co-first authors of this paper, and CUHK is the first corresponding author of this paper. First Corresponding Author of this paper.
The cytosolic oxygen receptor FIH, a 2-oxoglutarate (2OG) and Fe(II)-dependent oxidase containing the JmjC structural domain, is able to catalyze the post-translational modification of hydroxylation of a variety of substrate proteins, including HIF-α, which is a potential target for the treatment of lipid metabolic diseases. The team pre-discovered the Tyr102 variant pocket of FIH and further designed ZG-2291, a potent reversible inhibitor of FIH in vivo, as well as observed for the first time in a crystal structure that the conformation of the flexible side chain of FIH Lys106 can be stabilized by a small molecule ligand (ZG-2291) (Angew. Chem. Int. Ed. 2024, 63, e202410438).
In view of the difficulties in achieving long-lasting and controllable inhibition of FIH by the currently reported FIH-competitive reversible inhibitors, this study innovatively combined photochemical modulation with covalent inhibition, and successfully obtained the lysine-targeted photo-inducible covalent moiety, o-nitrobenzyl alcohol (o-NBA), in the pharmacophore of ZG-2291 through precise molecular design. The lysine-targeted photo-inducible and irreversible FIH covalent inhibition of NBA-ZG-2291 was successfully obtained through the precise molecular design of ZG-2291, which can specifically capture the Lys106 residue in the FIH metastable pocket through the photoclick reaction under light excitation to form a stable indazolone covalent complex and realize the temporally and spatially controllable, highly selective, and long-lasting inhibition of the target proteins. It was further shown that the photoregulation of the transcriptome by NBA-ZG-2291 was highly correlated with FIH knockdown. This study realizes for the first time the photocontrolled lysine-targeted covalent irreversible inhibition of the cellular oxygen receptor FIH, which provides a new chemical tool for the in-depth study of the complex regulatory mechanism of the cellular oxygen sensing pathway, and conceptually verifies the feasibility of the long-lasting inhibition of FIH through covalent approach, and also provides a new idea for the design of protein covalent inhibitors.
Design Ideas for the Photocontrolled Lysine-Targeted FIH Covalent Inhibitor NBA-ZG-2291
This research work was supported by the Excellent Youth Fund Project of National Natural Science Foundation of China, Xingdao Scholars Program of China Pharmaceutical University, National Key Laboratory of Multi-targeted Natural Drugs, Jiangsu Key Laboratory of Drug Molecular Design and Optimization of Pharmacogenetic Properties, Jiangsu Universities' Advantageous Discipline Construction Engineering Project, and China Postdoctoral Science Fund Facet Project.
Article link: https://pubs.acs.org/doi/10.1021/jacs.5c01935
