Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow 226 001, India.
J Med Chem. 2013 Feb 14;56(3):924-39. doi: 10.1021/jm301407k. Epub 2013 Jan 30.
To understand the influence of different hydrophobic amino acids at "a" and "d" positions of a heptad repeat sequence on antimicrobial, cytotoxic, and antiendotoxin properties, four 15-residue peptides with leucine (LRP), phenylalanine (FRP), valine (VRP), and alanine (ARP) residues at these positions were designed, synthesized, and characterized. Although valine is similarly hydrophobic to leucine and phenylalanine, VRP showed significantly lesser cytotoxicity than LRP and FRP; further, the replacement of leucines with valines at "a" and "d" positions of melittin-heptads drastically reduced its cytotoxicity. However, all four peptides exhibited significant antimicrobial activities that correlate well with their interactions with mammalian and bacterial cell membranes and the corresponding lipid vesicles. LRP most efficiently neutralized the LPS-induced pro-inflammatory mediators like NO, TNF-α, and IL-6 in macrophages followed by FRP, VRP, and ARP. The results could be useful for designing short antimicrobial and antiendotoxin peptides with understanding the basis of their activity.
为了了解七肽重复序列“a”和“d”位置上不同疏水性氨基酸对抗菌、细胞毒性和抗内毒素特性的影响，设计、合成并表征了四个具有亮氨酸（LRP）、苯丙氨酸（FRP）、缬氨酸（VRP）和丙氨酸（ARP）残基的 15 个残基肽。尽管缬氨酸与亮氨酸和苯丙氨酸具有相似的疏水性，但 VRP 的细胞毒性明显小于 LRP 和 FRP；此外，蜂毒素七肽的“a”和“d”位置上的亮氨酸被缬氨酸取代后，其细胞毒性大大降低。然而，所有四个肽都表现出显著的抗菌活性，这与其与哺乳动物和细菌细胞膜以及相应的脂质体的相互作用密切相关。LRP 最有效地中和了 LPS 诱导的巨噬细胞中促炎介质，如 NO、TNF-α 和 IL-6，其次是 FRP、VRP 和 ARP。这些结果对于设计具有抗菌和抗内毒素活性的短肽具有重要意义，有助于了解其作用机制。
