Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
Department of Chemistry, Texas A&M University. Texas, United States of America.
PLoS One. 2014 Mar 6;9(3):e89617. doi: 10.1371/journal.pone.0089617. eCollection 2014.
A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f) are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b) are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.
文库的肽模拟物被组合成双体，以三嗪为核心。药效团对应于神经营养因子多肽神经生长因子（NGF）、脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）的β-转角。它们分别是 TrkC、TrkA 和 TrkB 受体的天然配体。二价模拟物中每个单体的连接子长度和侧链取向被系统改变，并评估了这些变化对每个配体功能的影响。虽然单价肽模拟物没有可检测的结合或生物活性，但有 4 种二价肽模拟物（2c、2d、2e、3f）是具有拮抗活性的选择性 TrkC 配体，2 种二价肽模拟物（1a、1b）是具有拮抗活性的 TrkC 和 TrkA 配体。所有这些二价化合物都能阻断配体依赖性受体激活和细胞存活，而不影响神经突生成分化。这项工作增加了我们对神经营养因子如何通过 Trk 受体发挥作用的理解，并证明肽模拟物可以被设计成选择性地干扰特定的生物学信号，并且可以用作药理学探针或治疗性先导物。在药效团中改变亚基的侧链、连接子长度和序列取向的概念提供了一种简单的模块化方法，可以生成具有多样化生物活性的更大文库。
