Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.
Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.
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DOI：
10.1039/d1ob01120k
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发表时间：
2021-09-22
影响因子：
3.2
通讯作者：
Burke TR Jr
中科院分区：
文献类型：
--
作者：
Hymel D;Tsuji K;Grant RA;Chingle RM;Kunciw DL;Yaffe MB;Burke TR Jr
靶向蛋白-蛋白相互作用（PPIs）已成为抗癌治疗发展的一个重要发现领域。对于磷酸化依赖性PPIs，如polo样激酶1 (Plk1) polo-box结构域（PBD），磷酸化的蛋白残基可以提供高亲和力的识别和结合靶蛋白热点。开发Plk1 PBD拮抗剂尤其具有挑战性，如果仅仅依赖于磷酸化结合口袋内部和近端相互作用。幸运的是，磷酸依赖的PPI拮抗剂的亲和力可以通过利用磷酸结合位点和可能在配体结合上显示的隐藏的“神秘”口袋的相互作用而显着增强。在我们目前的论文中，我们描述了针对Plk1 PBD的大环肽模拟物的设计和合成，其特点是一个新的谷氨酸类似物，同时作为一个闭合环的连接，提供了一个隐式结合口袋的通道，同时实现了磷苏氨酸（pT）残基的适当取向，以实现在磷酸化结合口袋中的最佳相互作用。用这种新的氨基酸类似物制备的大环引入了在开链线性亲本肽中没有发现的额外的氢键相互作用。值得注意的是，这种新的基于谷氨酸的氨基酸类似物代表了极高亲和力配体的第一个例子，其中从pT-2位置进入隐口袋的残基不是基于组氨酸。设计和合成这些新的大环肽模拟物的概念应该对针对Plk1 PBD的进一步研究和潜在的针对其他PPI靶点的配体有帮助。一种新的大环肽策略，利用谷氨酸类似物，可以作为烷基化组氨酸的替代品。
Targeting protein – protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phospho-dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden “cryptic” pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets. A novel macrocyclic peptide strategy utilizing a glutamic acid analog that can work as an alkylated histidine replacement.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
4
作者：
Liu F;Park JE;Qian WJ;Lim D;Scharow A;Berg T;Yaffe MB;Lee KS;Burke TR Jr
通讯作者：
Burke TR Jr
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
6.8
作者：
Ghadie, Mohamed A.;Coulombe-Huntington, Jasmin;Xia, Yu
通讯作者：
Xia, Yu
影响因子：
1.8
作者：
Hanessian, S;Margarita, R
通讯作者：
Margarita, R