Massa Stephen M, Xie Youmei, Longo Frank M
Department of Neurology, VAMC/UC San Francisco, CA 94121, USA.
J Mol Neurosci. 2003;20(3):323-6. doi: 10.1385/JMN:20:3:323.
Factors limiting the therapeutic application of neurotrophins to neurodegenerative diseases include poor stability and CNS penetration. Moreover, certain neurotrophin effects, such as promotion of neuronal death via interaction with the p75NTR receptor, might further limit their application. We have proposed that development of small molecule mimetics of neurotrophins might serve to overcome these limitations. In previous work, our laboratory established the proof-of-principle that mimetics of specific nerve growth factor (NGF) domains could prevent neuronal death. Peptidomimetics of the loop 1 domain prevent death via p75NTR-dependent signaling and peptidomimetics of the loop 4 domain prevent death via Trk-related signaling. In current work we are designing pharmacophore queries corresponding to loop domains 1 or 4 that incorporate features of the NGF crystal structure along with features derived from peptidomimetic structure-activity-relationships. Screening of in silico databases containing non-peptide, small molecules has identified a number of candidate NGF domain mimetics. Preliminary assessment of these compounds using neurotrophin bioassays indicates that several are capable of preventing neuronal death. Ongoing studies will determine whether these compounds act via p75NTR or Trk receptors.
限制神经营养因子在神经退行性疾病中治疗应用的因素包括稳定性差和难以穿透中枢神经系统。此外，某些神经营养因子的作用，如通过与p75NTR受体相互作用促进神经元死亡，可能会进一步限制它们的应用。我们提出，开发神经营养因子的小分子模拟物可能有助于克服这些限制。在之前的工作中，我们实验室确立了一个原理证明，即特定神经生长因子（NGF）结构域的模拟物可以防止神经元死亡。环1结构域的拟肽通过p75NTR依赖性信号传导防止死亡，环4结构域的拟肽通过Trk相关信号传导防止死亡。在当前的工作中，我们正在设计与环结构域1或4相对应的药效团查询，这些药效团结合了NGF晶体结构的特征以及源自拟肽结构-活性-关系的特征。对包含非肽小分子的虚拟数据库进行筛选，已鉴定出许多候选的NGF结构域模拟物。使用神经营养因子生物测定法对这些化合物进行的初步评估表明，其中几种能够防止神经元死亡。正在进行的研究将确定这些化合物是否通过p75NTR或Trk受体起作用。
