Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease
Human glutaminyl cyclase (hQC) is drawing considerable attention and emerging as a potential druggable target for Alzheimer's disease (AD) due to its close involvement in the pathology of AD via the post-translational pyroglutamate modification of amyloid-β. A recent phase 2a study has shown pr...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1209863/full |
| _version_ | 1797755325156163584 |
|---|---|
| author | Daoyuan Chen Qingxiu Chen Xiaofei Qin Peipei Tong Liping Peng Tao Zhang Chunli Xia |
| author_facet | Daoyuan Chen Qingxiu Chen Xiaofei Qin Peipei Tong Liping Peng Tao Zhang Chunli Xia |
| author_sort | Daoyuan Chen |
| collection | DOAJ |
| description | Human glutaminyl cyclase (hQC) is drawing considerable attention and emerging as a potential druggable target for Alzheimer's disease (AD) due to its close involvement in the pathology of AD via the post-translational pyroglutamate modification of amyloid-β. A recent phase 2a study has shown promising early evidence of efficacy for AD with a competitive benzimidazole-based QC inhibitor, PQ912, which also demonstrated favorable safety profiles. This finding has sparked new hope for the treatment of AD. In this review, we briefly summarize the discovery and evolution of hQC inhibitors, with a particular interest in classic Zinc binding group (ZBG)-containing chemicals reported in recent years. Additionally, we highlight several high-potency inhibitors and discuss new trends and challenges in the development of QC inhibitors as an alternative and promising disease-modifying therapy for AD. |
| first_indexed | 2024-03-12T17:46:12Z |
| format | Article |
| id | doaj.art-0b7f24f1858e4cda8f24dd7fca96978a |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-03-12T17:46:12Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-0b7f24f1858e4cda8f24dd7fca96978a2023-08-03T16:35:53ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-08-011510.3389/fnagi.2023.12098631209863Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's diseaseDaoyuan Chen0Qingxiu Chen1Xiaofei Qin2Peipei Tong3Liping Peng4Tao Zhang5Chunli Xia6School of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaFujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Institute of Basic Medicine, Fujian Medical University, Fuzhou, ChinaSchool of Bioengineering, Zunyi Medical University, Zhuhai, ChinaHuman glutaminyl cyclase (hQC) is drawing considerable attention and emerging as a potential druggable target for Alzheimer's disease (AD) due to its close involvement in the pathology of AD via the post-translational pyroglutamate modification of amyloid-β. A recent phase 2a study has shown promising early evidence of efficacy for AD with a competitive benzimidazole-based QC inhibitor, PQ912, which also demonstrated favorable safety profiles. This finding has sparked new hope for the treatment of AD. In this review, we briefly summarize the discovery and evolution of hQC inhibitors, with a particular interest in classic Zinc binding group (ZBG)-containing chemicals reported in recent years. Additionally, we highlight several high-potency inhibitors and discuss new trends and challenges in the development of QC inhibitors as an alternative and promising disease-modifying therapy for AD.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1209863/fullAlzheimer's diseasehuman glutaminyl cyclaseamyloid-βpyroglutamate modificationQC inhibitorPQ912 |
| spellingShingle | Daoyuan Chen Qingxiu Chen Xiaofei Qin Peipei Tong Liping Peng Tao Zhang Chunli Xia Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease Frontiers in Aging Neuroscience Alzheimer's disease human glutaminyl cyclase amyloid-β pyroglutamate modification QC inhibitor PQ912 |
| title | Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease |
| title_full | Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease |
| title_fullStr | Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease |
| title_full_unstemmed | Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease |
| title_short | Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease |
| title_sort | development and evolution of human glutaminyl cyclase inhibitors qcis an alternative promising approach for disease modifying treatment of alzheimer s disease |
| topic | Alzheimer's disease human glutaminyl cyclase amyloid-β pyroglutamate modification QC inhibitor PQ912 |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1209863/full |
| work_keys_str_mv | AT daoyuanchen developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT qingxiuchen developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT xiaofeiqin developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT peipeitong developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT lipingpeng developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT taozhang developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease AT chunlixia developmentandevolutionofhumanglutaminylcyclaseinhibitorsqcisanalternativepromisingapproachfordiseasemodifyingtreatmentofalzheimersdisease |