Porter Emilie A, Weisblum Bernard, Gellman Samuel H
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Am Chem Soc. 2005 Aug 17;127(32):11516-29. doi: 10.1021/ja0519785.
We report structure-activity trends among helix-forming beta-amino acid oligomers that are intended to mimic alpha-helical host-defense peptides. Parallel synthesis of two small, focused beta-peptide libraries allowed us to identify relatively short (11-residue) beta-peptides that display antimicrobial activity. These beta-peptides exhibit selectivity for bacteria relative to human red blood cells. A large hydrophobic helical surface is necessary for antimicrobial activity. Longer analogues (16 residues) of the most active library members were prepared and evaluated. Some of these longer beta-peptides showed very good antimicrobial activity, but none was more active than a previously reported beta-peptide [Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565]. The extensive literature on alpha-helical host-defense peptides and related alpha-peptides indicates that such molecules are seldom active at concentrations below 1 microg/mL, and our results suggest that amphiphilic helical beta-peptides are subject to a comparable limit.
我们报道了旨在模拟α-螺旋宿主防御肽的形成螺旋的β-氨基酸寡聚物的构效关系趋势。两个小型、聚焦的β-肽文库的平行合成使我们能够鉴定出具有抗菌活性的相对较短（11个残基）的β-肽。这些β-肽相对于人类红细胞对细菌具有选择性。较大的疏水螺旋表面对于抗菌活性是必需的。制备并评估了最具活性文库成员的较长类似物（16个残基）。其中一些较长的β-肽显示出非常好的抗菌活性，但没有一个比先前报道的β-肽[波特，E.A.；王，X.；李，H.-S.；韦斯布卢姆，B.；盖尔曼，S.H.《自然》2000年，404卷，565页]更具活性。关于α-螺旋宿主防御肽和相关α-肽的大量文献表明，此类分子在浓度低于1微克/毫升时很少有活性，我们的结果表明两亲性螺旋β-肽也受到类似的限制。
