Recently, The Huang Zhangjian team at our university and the Chen Chang team at the Institute of Biophysics, Chinese Academy of Sciences, jointly published a study titled “S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory” in the journal Redox Biology. They successfully developed SNOTAC, a precision nitrosylation regulatory molecule distinct from traditional nitric oxide (NO) donors, offering a novel therapeutic strategy for improving memory impairment.
Nitrosylation of CaMKIIα: A Novel Mechanism Mediating Learning and Memory
Chen Chang's team has long investigated the relationship between protein nitrosylation and disease. Their earlier work revealed that in the hippocampal tissue of elderly individuals and aged mice, the expression level of GSNOR—an enzyme responsible for denitrosylation—was significantly elevated. Conversely, the level of sulfhydryl nitrosylation (S-nitros(yl)ation) on Ca2+/calmodulin-dependent protein kinase IIa (Ca2+/calmodulin-dependent protein kinase IIa, CaMKIIα), a key protein for learning and memory, was markedly reduced (J Neurosci. 2017;37(40):974). CaMKIIα) exhibited markedly reduced levels of sulfhydryl nitrosylation (S-nitros(yl)ation) (J Neurosci. 2017;37(40):9741-9758). These critical clues suggest that diminished CaMKIIα nitrosylation may be closely linked to age-related impairments in learning and memory.
Chen Chang's team further explored the specific role and causal relationship of this modification in learning and memory, demonstrating for the first time that CaMKIIα S-nitrosylation represents a novel key post-translational modification mediating physiological learning and memory functions, independent of the widely recognized phosphorylation modification. In-depth mechanistic studies revealed that loss of nitrosylation in CaMKIIα leads to abnormal presynaptic vesicle release during neural quiescence (“leakage” effect), establishing this as a novel mechanism for learning and memory decline and offering fresh insights into age-related memory impairment.
Precision Nitrosylation Intervention: From Concept to Practice
Having established the core regulatory role of CaMKIIα nitrosylation in memory, the Huang Zhangjian research group further explored whether precisely enhancing its modification levels could reverse memory impairment. Unlike post-translational modifications such as acetylation or phosphorylation, protein nitrosylation lacks universal synthases and primarily occurs through the reaction of nitric oxide with sulfhydryl groups. Traditional nitrosylation regulation methods (modulating NO levels) often employ a “shotgun” approach, non-specifically affecting numerous proteins and potentially triggering off-target effects. Recently, the Huang Zhangjian team developed a “bullet” strategy to achieve precise nitrosylation modification of multiple targets (J Am Chem Soc. 2025, 147(30): 26726−26738). For precise regulation of CaMKIIα nitrosylation, the team developed another universal “glue” strategy—using small molecules to bring the target protein closer to nitric oxide synthase, enabling the NO it produces to selectively act on the target protein and achieve precise nitrosylation modification. They innovatively designed and synthesized the nitrosylation-targeted chimera SNOTAC.
The precision nitrosylation regulatory molecule SNOTAC developed in this study specifically bridges neuronal nitric oxide synthase (nNOS) with the target protein CaMKIIα, thereby precisely and selectively enhancing CaMKIIα nitrosylation levels. Intranasal administration of SNOTAC effectively restored memory function in mice with learning and memory deficits caused by brain-specific GSNOR overexpression (mimicking age-related decreased nitrosylation levels). This strategy holds potential for extension to other diseases and targets, while also fostering novel approaches to drug discovery. By leveraging a deep understanding of the relationship between specific protein nitrosylation and disease progression, precise modulation of nitrosylation could enable therapeutic interventions. This approach may partially address the bottleneck of limited drug targets in pharmaceutical development, offering fresh perspectives and methodologies for innovative drug research.
Precise Nitrosylation of CaMKIIα by SNOTAC Improves Learning and Memory Impairment
This study developed candidate drugs based on key nitrosylation sites of CaMKIIα, a critical target for age-related memory decline. It proposed a novel drug development strategy—the “glue” strategy—distinct from traditional NO donors. The SNOTAC molecules developed under this strategy precisely target key redox modifications to improve learning and memory deficits, providing a successful model for targeted nitrosylation intervention.
Researcher Chang Chen from the Institute of Biophysics, Chinese Academy of Sciences, and Professor Zhangjian Huang from China Pharmaceutical University served as co-corresponding authors. Dr. Boyu Chu and Associate Researcher Xinhua Qiao from Chang Chen's group, along with postdoctoral researcher Hui Ye from Zhangjian Huang's group, are co-first authors. This research received funding from the National Key R&D Program of China, the Strategic Priority Research Program (B) of the Chinese Academy of Sciences, the National Natural Science Foundation of China, and the Beijing Natural Science Foundation.
Article link: https://doi.org/10.1016/j.redox.2025.103784
