Macrocyclic statine-based inhibitors of BACE-1
Macrocyclic statine-based inhibitors of BACE-1
复制标题
DOI：
10.1002/cbic.200700383
复制
发表时间：
2007-11-23
期刊：
影响因子：
3.2
通讯作者：
Moroder, Luis
中科院分区：
文献类型：
--
作者：
Barazza, Alessandra;Goetz, Marion;Moroder, Luis
基于与BACE-1复合的羟乙烯-八肽OM 00 -3的X-射线共晶结构，建立了底物衍生的他汀肽与乙酰胆碱酯酶结合的最低序列要求。有了这些信息，大环化合物的构象限制和preorganize的肽骨架的熵有利于结合酶的活性位点裂缝的设计。通过在P2和P3'位置的两个乙酰基残基之间通过亚苯基-1，3-二甲胺进行侧链-侧链环闭合，获得了23元环结构;该结构保留了肽骨架的延伸构象，包括与活性中心的两个乙酰基残基紧密相互作用的过渡态类似物他汀。通过核磁共振结构分析验证了抑制剂分子的构象预组织，然后通过BACE-1/抑制剂复合物的晶体结构证实了这一点。详细的洞察到这种大环抑制剂的结合模式解释了其在无细胞测定中的适度结合亲和力（Ki =2.5 μ m），并产生了宝贵的信息，可能的结构优化，鉴于缺乏立体冲突的大环与flop域的酶。
Minimal sequence requirements for binding of substrate-derived statine peptides to the aspartyl enzyme were established on the basis of the X-ray cocrystal structure of the hydroxyethylene-octapeptide OM00-3 in complexation with BACE-1. With this information to hand, macrocyclic compounds that conformationally restrict and preorganize the peptide backbone for an entropically favoured binding to the enzyme active site cleft were designed. By means of a side chain-to-side chain ring closure between two aspartyl residues in the P2 and P3' positions through phenylene-1,3-dimethanamine, a 23-membered ring structure was obtained; this structure retained an extended conformation of the peptide backbone, including the transition state analogue statine for tight interactions with the two aspartyl residues of the active centre. The conformational preorganization of the inhibitor molecule was verified by NMR structural analysis and was then confirmed by the crystal structure of the BACE-1/inhibitor complex. Detailed insights into the binding mode of this macrocyclic inhibitor explained its moderate binding affinity in cell-free assays (K-i=2.5 mu m) and yielded precious information for possible structural optimization in view of the lack of steric clashes of the macrocycle with the flop domain of the enzyme.