Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, MA 02155, USA.
Chembiochem. 2012 Jul 9;13(10):1490-6. doi: 10.1002/cbic.201200175. Epub 2012 Jun 11.
Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples to produce peptide bicycles with higher affinity, selectivity, and resistance to degradation. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homology 2 (SH2) domain of growth-factor-bound protein 2 (Grb2). Several homodetic peptide bicycles were synthesized entirely on-resin with high yields. Two rounds of iterative design produced peptide bicycle BC1, which is 60 times more potent than G1 and 200 times more selective. Moreover, BC1 is completely intact after 24 hours in buffered human serum, conditions under which G1 is completely degraded. Our peptide-bicycle approach holds promise for the development of selective inhibitors of SH2 domains and other phosophotyrosine (pTyr)-binding proteins, as well as inhibitors of many other protein-protein interactions.
将短肽开发成有用的探针和治疗先导物仍然是一个具有挑战性的难题。结构刚性化是一种已被证实的方法，可以改善短肽的性质。在这项工作中，我们报告了一种通过引入侧链到侧链订书钉来稳定肽大环的策略，从而产生具有更高亲和力、选择性和抗降解能力的肽自行车。我们已经将这种策略应用于 G1，这是一种结合生长因子结合蛋白 2（Grb2）SH2 结构域的 11 个残基肽大环。几种同源肽自行车完全在树脂上合成，产率很高。两轮迭代设计产生了肽自行车 BC1，其效力比 G1 高 60 倍，选择性高 200 倍。此外，在缓冲的人血清中 24 小时后，BC1 仍然完全完整，而 G1 则完全降解。我们的肽自行车方法有望开发 SH2 结构域和其他磷酸酪氨酸（pTyr）结合蛋白的选择性抑制剂，以及许多其他蛋白质-蛋白质相互作用的抑制剂。
