Unnatural Amino Acid Side Chains as S1, S1′, and S2′ Probes Yield Cationic Antimicrobial Peptides with Stability toward Chymotryptic Degradation
Unnatural Amino Acid Side Chains as S1, S1′, and S2′ Probes Yield Cationic Antimicrobial Peptides with Stability toward Chymotryptic Degradation
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DOI：
10.1021/jm1006337
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发表时间：
2010-08-12
影响因子：
7.3
通讯作者：
Svenson, Johan
中科院分区：
文献类型：
--
作者：
Karstad, Rasmus;Isaksen, Geir;Svenson, Johan
这项工作描述了如何在P1，P1 '和P2'位置系统地掺入一系列非天然氨基酸衍生物，从而产生对胰凝乳蛋白酶降解具有稳定性的短乳铁蛋白基阳离子抗菌肽。必要的药效团设置的肽降解胰凝乳蛋白酶，和严重截断的天然三肽被迅速消化，尽管其短序列。降解研究表明，可以通过改变与活性位点周围每个亚位点的结合而不牺牲抗微生物活性来延长半衰期。通过使用天然肽底物，以不可行的方式揭示了重要的结构和机制特征。通常适用于一系列相关肽的结果进一步表明，通过掺入色氨酸和精氨酸的不同类似物，不仅S1口袋，而且对S1'位点的研究明显较少，可用于控制蛋白水解稳定性。
This work describes how the systematic incorporation of a range of unnatural amino acid derivatives in the PI, P1', and P2' positions allows for the generation of short lactoferricin based cationic antimicrobial peptides with a stability toward chymotryptic degradation. The necessary pharmacophore sets the peptides up for degradation by chymotrypsin, and a heavily truncated native tripeptide was rapidly digested despite its short sequence. Degradation studies indicated that increased half-lives could be obtained by altering the binding to each subsite surrounding the active site without sacrificing the antimicrobial activity. Important structural and mechanistic features were revealed in a fashion not feasible through the use of native peptide substrates. The results, which are generally applicable to a range of relevant peptides, further show that not only the S I pocket, but also to the notably less studied S1' site can be used to control the proteolytic stability by incorporating different analogues of tryptophan and arginine.