Amijee Hozefa, Madine Jill, Middleton David A, Doig Andrew J
Senexis Limited, Babraham Research Campus, Cambridge CB2 4AT, UK.
Biochem Soc Trans. 2009 Aug;37(Pt 4):692-6. doi: 10.1042/BST0370692.
The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Abeta (amyloid beta-peptide) in AD (Alzheimer's disease), asyn (alpha-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Abeta toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Abeta-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.
多种肽或蛋白质的聚集与疾病的发生有关，包括阿尔茨海默病中的β淀粉样蛋白（Aβ）、帕金森病中的α-突触核蛋白（α-syn）以及2型糖尿病中的胰岛淀粉样多肽（amylin）。多种淀粉样蛋白ogenic蛋白质通常可以被切割成少至五个残基的自我识别元件（SRE），该元件保留聚集能力。SRE可作为聚集抑制剂的起点。特别是，N-甲基化的SRE可以在一侧与靶标结合，但在其甲基化面上氢键被阻断，从而干扰进一步的组装。我们应用这一策略开发Aβ毒性抑制剂。在相同条件下，使用生物物理和毒性测定法对我们的化合物以及文献中的一系列化合物进行了比较。两种带有非天然侧链的N-甲基化D-肽抑制剂最为有效，并且在低至10 nM的浓度下就能逆转Aβ诱导的长时程增强（LTP）抑制。通过固态核磁共振确定了α-syn中的一个SRE（VAQKTV）。当VAQKTV被N-甲基化时，它能够破坏α-syn的聚集。胰岛淀粉样多肽SRE的N-甲基化衍生物也能够抑制胰岛淀粉样多肽的聚集。
