X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model

  • J Med Chem. 2024 Jun 13;67(11):8730-8756. doi: 10.1021/acs.jmedchem.4c00049.
Jun Mou  1 ,  Xiang-Li Ning  1 ,  Xin-Yue Wang  1 ,  Shu-Yan Hou  1 ,  Fan-Bo Meng  1 ,  Cong Zhou  1 ,  Jing-Wei Wu  1 ,  Chunyan Li  1 ,  Tao Jia  1 ,  Xiaoai Wu  2 ,  Yong Wu  1 ,  Yongping Chen  3 ,  Guo-Bo Li  1
Affiliations
  • 1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 2. Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 38817193 DOI: 10.1021/acs.jmedchem.4c00049
Abstract

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

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