Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, 060031 Bucharest, Romania.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
J Med Chem. 2022 Jan 13;65(1):217-233. doi: 10.1021/acs.jmedchem.1c01303. Epub 2021 Dec 28.
Cognitive impairment and learning ability of the brain are directly linked to synaptic plasticity as measured in changes of long-term potentiation (LTP) and long-term depression (LTD) in animal models of brain diseases. LTD reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. AMPA receptor endocytosis is initiated by dephosphorylation of Tyr on the C-terminus of the AMPAR subunit GluA2. The brain-specific striatal-enriched protein tyrosine phosphatase (STEP) is responsible for this process. To identify new, highly effective inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization, we performed structure-based design of peptides able to inhibit STEP-GluA2-CT complex formation. Two short peptide derivatives were found as efficient inhibitors. Our experiments evidenced that both peptides restore the memory deficits and display anxiolytic and antidepressant effects in a scopolamine-treated rat model. The interference peptides identified and characterized here represent promising lead compounds for novel cognitive enhancers and/or behavioral modulators.
大脑的认知障碍和学习能力与突触可塑性直接相关，突触可塑性可以通过对脑疾病动物模型中长时程增强（LTP）和长时程抑制（LTD）的变化来测量。LTD 反映了基于靶向网格蛋白介导的内吞作用的突触 AMPA 受体含量的持续减少。AMPA 受体内吞作用是由 AMPAR 亚基 GluA2 的 C 末端 Tyr 的去磷酸化引发的。脑特异性纹状体丰富的蛋白酪氨酸磷酸酶（STEP）负责该过程。为了鉴定新型、高效的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）内化抑制剂，我们进行了基于结构的肽设计，以抑制 STEP-GluA2-CT 复合物的形成。发现了两种短肽衍生物作为有效的抑制剂。我们的实验证明，这两种肽都能恢复记忆缺陷，并在东莨菪碱处理的大鼠模型中表现出抗焦虑和抗抑郁作用。这里鉴定和表征的干扰肽代表了新型认知增强剂和/或行为调节剂的有前途的先导化合物。
