Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy.
Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy.
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DOI：
10.1021/jm801072v
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发表时间：
2009-04
影响因子：
7.3
通讯作者：
K. S. Orwig;McKensie R. Lassetter;M. Hadden;Thomas A. Dix
中科院分区：
文献类型：
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作者：
K. S. Orwig;McKensie R. Lassetter;M. Hadden;Thomas A. Dix
神经降压素 (8-13) 和两种相关类似物被用作模型系统，直接比较代表常用和新型加帽基团的各种 N 端肽修饰。每个 N 端修饰都阻止氨肽酶裂解，但令人惊讶的是其抑制其他位点裂解的能力不同，这种现象归因于长程构象效应。没有一个封端基团本质上对人神经降压素受体 1 (hNTR1) 结合亲和力或受体激动作用有害。尽管最稳定的肽表现出最低的结合亲和力并且是效力最弱的受体激动剂，但它们产生最大的体内效应。在所研究的参数中，只有稳定性与体内功效显着相关，这表明 NTR1 结合亲和力的降低可以通过增加体内稳定性来抵消。
Neurotensin(8-13) and two related analogues were used as model systems to directly compare various N-terminal peptide modifications representing both commonly used and novel capping groups. Each N-terminal modification prevented aminopeptidase cleavage but surprisingly differed in its ability to inhibit cleavage at other sites, a phenomenon attributed to long-range conformational effects. None of the capping groups were inherently detrimental to human neurotensin receptor 1 (hNTR1) binding affinity or receptor agonism. Although the most stable peptides exhibited the lowest binding affinities and were the least potent receptor agonists, they produced the largest in vivo effects. Of the parameters studied only stability significantly correlated with in vivo efficacy, demonstrating that a reduction in binding affinity at NTR1 can be countered by increased in vivo stability.