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Outline
The development of therapeutic interventions for central nervous system (CNS) diseases poses significant challenges. These challenges are primarily attributable to the limitations imposed by the blood-brain barrier (BBB) permeability and the inherent complexity of protein aggregates. Targeted protein degradation (TPD) technology selectively removes pathogenic proteins through the ubiquitin-proteasome system or lysosomal pathways, offering a new strategy for CNS treatment. In comparison with conventional small molecule drugs, TPD employs an event-driven mode of action, capable of degrading β-amyloid and other "undruggable" targets, and demonstrating efficacy at sub-chemometric doses. This is anticipated to markedly reduce the complexity of CNS delivery. The disconnecting of pharmacodynamics and pharmacokinetics further reduces the risk of off-targeting, making it particularly suitable for the CNS, a therapeutic area that requires a high degree of drug safety. Three CNS degraders have already entered clinical trials. This review comprehensively elaborates on the application progress of TPD technologies based on different degradation systems in the treatment of CNS diseases, systematically analyzes the advantages and limitations of each technology, and discusses the common challenges and general optimization strategies for TPD application in CNS disease therapy. The findings aim to provide new insights for the in-depth application of TPD technology in the treatment of CNS diseases.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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