公开(公告)号：US5221732A

公开(公告)日：1993-06-22

申请号：US280363

申请日：1988-12-06

申请人： Hao-Chia Chen ,  Judith H. Brown ,  John L. Morell ,  Charng-Ming Huang

发明人： Hao-Chia Chen ,  Judith H. Brown ,  John L. Morell ,  Charng-Ming Huang

IPC分类号： A61K38/00 ,  C07K14/46

CPC分类号： C07K14/46 ,  A61K38/00

摘要： Peptides which exhibit improved broad spectrum antimicrobial activity are designed and synthesized based on the peptide sequences of magainin or PGS peptides. The modified peptide analogues are synthesized by replacing low helical potential amino acid residues with high helical potential residues and modifying the two termini in order to enhance the amphiphilic structures as well as to prolong antimicrobial activity by lowering their susceptibility to protease degradation. For example, low propensity residues within a strategic region of magainin II, e.g. Ser.sup.8, Gly.sup.13 and Gly.sup.18 are modified with Ala which is known to have high propensity. Amidation of Ser.sup.23, and acylation of Gly.sup.1 with acetyl or beta-alanyl and substitution of Gly.sup.1 with beta-alanine are carried out in order to lower the susceptibility to exopeptidase action. A D-Ala modification for disrupting a stretch of the helical structure is also prepared so as to demonstrate the importance of an amphiphilic helical structure for antimicrobial activity. The modified peptide analogues exhibit an increase of up to two orders of magnitude in antimicrobial activity and, in the most favorable case, no appreciable increase in hemolytic activity over magainin 1.

摘要翻译： 基于magainin或PGS肽的肽序列设计并合成显示出改善的广谱抗微生物活性的肽。 通过用高螺旋电位残基替代低螺旋电位氨基酸残基并修饰两个末端来合成修饰的肽类似物，以增强两亲性结构以及通过降低其对蛋白酶降解的易感性来延长抗微生物活性。 例如，在magainin II的战略区域内的低倾向残基，例如， Ser8，Gly13和Gly18用已知具有高倾向的Ala修饰。 进行Ser23的酰胺化和Gly1与乙酰基或β-丙氨酰的酰化以及用β-丙氨酸取代Gly1以降低对外肽酶作用的易感性。 还制备用于破坏螺旋结构的拉伸的D-Ala修饰，以证明两亲性螺旋结构对于抗微生物活性的重要性。 修饰的肽类似物在抗菌活性中表现出高达两个数量级的增加，并且在最有利的情况下，相对于magainin 1，溶血活性没有明显增加。