Design of potent peptide mimetics of brain-derived neurotrophic factor
Design of potent peptide mimetics of brain-derived neurotrophic factor
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DOI：
10.1074/jbc.m303209200
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发表时间：
2003-07-11
影响因子：
4.8
通讯作者：
Hughes, RA
中科院分区：
文献类型：
--
作者：
O'Leary, PD;Hughes, RA
脑源性神经营养因子（BDNF）具有治疗人类神经退行性疾病的潜力。然而，神经营养因子在临床试验中普遍缺乏成功，这使得人们认为低分子量神经营养药物可能是更好的治疗药物。在这里，我们描述了小的，二聚体肽设计模仿一对溶剂暴露的环重要的BDNF受体，trkB的结合和激活。构成二聚体的单体组分是基于BDNF的单环（环2）的单环单体肽模拟物，我们先前已经证明其是BDNF介导的神经元存活的抑制剂（O ′ Leary，P.D.，和Hughes，R. A.等人（1998）J. Neurochem. 70，1712 - 1721）。双环二聚肽作为脑源性神经营养因子的部分激动剂，促进培养物中胚胎鸡感觉神经元的存活。我们推断，这些化合物的效力和/或功效可以通过降低其二聚化接头的构象灵活性来改善。因此，我们设计了一种高度构象约束的三环二聚肽，并使用有效的，准一锅法合成它。虽然仍然是一种部分BDNF样激动剂，三环二聚体在体外促进神经元存活方面特别有效（EC 50 11 pM）。这里描述的肽，这是大大减少了与亲本蛋白质的大小相比，可以作为有用的先导化合物的发展，真正的神经营养药物，并表明基于结构的设计方法可用于获得有效的模拟物的其他生长因子，二聚化其受体。
Brain-derived neurotrophic factor ( BDNF) has potential for the treatment of human neurodegenerative diseases. However, the general lack of success of neurotrophic factors in clinical trials has led to the suggestion that low molecular weight neurotrophic drugs may be better agents for therapeutic use. Here we describe small, dimeric peptides designed to mimic a pair of solvent-exposed loops important for the binding and activation of the BDNF receptor, trkB. The monomer components that make up the dimers were based on a monocyclic monomeric peptide mimic of a single loop of BDNF ( loop 2) that we had previously shown to be an inhibitor of BDNF-mediated neuronal survival ( O'Leary, P. D., and Hughes, R. A. ( 1998) J. Neurochem. 70, 1712 1721). Bicyclic dimeric peptides behaved as partial agonists with respect to BDNF, promoting the survival of embryonic chick sensory neurons in culture. We reasoned that the potency and/or efficacy of these compounds might be improved by reducing the conformational flexibility about their dimerizing linker. Thus, we designed a highly conformationally constrained tricyclic dimeric peptide and synthesized it using an efficient, quasi-one-pot approach. Although still a partial BDNF-like agonist, the tricyclic dimer was particularly potent in promoting neuronal survival in vitro (EC50 11 pM). The peptides described here, which are greatly reduced in size compared with the parent protein, could serve as useful lead compounds for the development of true neurotrophic drugs and indicate that the structure-based design approach could be used to obtain potent mimetics of other growth factors that dimerize their receptors.