文献类型：期刊文献

英文题名：Design of novel antimicrobial peptide dimer analogues with enhanced antimicrobial activity in vitro and in vivo by intermolecular triazole bridge strategy

作者：Liu, Beijun[1,2];Huang, Haifeng[3];Yang, Zhibin[4];Liu, Beiyin[5];Gou, Sanhu[1];Zhong, Chao[2];Han, Xiufeng[2];Zhang, Yun[2];Ni, Jingman[1,2];Wang, Rui[1]

第一作者：Liu, Beijun

通信作者：Liu, BJ[1];Liu, BJ[2]

机构：[1]Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China;[2]Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China;[3]Shaanxi Prov Peoples Hosp, Xian 710068, Shanxi, Peoples R China;[4]Dali Univ, Key Lab Entomol Biopharmaceut R&D Yunnan Prov, Dali 671000, Peoples R China;[5]Gansu Univ Chinese Med, Affiliated Hosp, Lanzhou 730000, Peoples R China

第一机构：Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China;[2]corresponding author), Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China.

年份：2017

卷号：88

起止页码：115

外文期刊名：PEPTIDES

收录：;Scopus(收录号：2-s2.0-85008144058);WOS:【SCI-EXPANDED(收录号:WOS:000393930700015)】；

基金：This study was supported by the grants from the National Natural Science Foundation of China (Nos. 81273355, 81273440 and 91213302), the Key National S&T Program of the Ministry of Science and Technology (2012ZX09504001-003), Program for Changjiang Scholars and Innovative Research Team in University (IRT1137), Fundamental Research Funds for the Central Universities (lzujbky-2015-308).

语种：英文

外文关键词：Click chemistry; Dimer analogues; Antimicrobial activity; alpha Helical structure; Drug resistance

摘要：Currently, antimicrobial peptides have attracted considerable attention because of their broad-sprectum activity and low prognostic to induce antibiotic resistance. In our study, for the first time, a series of side chain hybrid dimer peptides J-AA (Anoplin-Anoplin), J-RR (RW-RW), and J-AR (Anoplin-RW) based on the wasp peptide Anoplin and the arginine- and tryptophan-rich hexapeptide RW were designed and synthesized by click chemistry, with the intent to improve the antimicrobial efficacy of peptides against bacterial pathogens. The results showed that all dimer analogues exhibited up to a 4-16 fold increase in antimicrobial activity compared to the parental peptides against bacterial strains. Furthermore, the antimicrobial activity was confirmed by time-killing kinetics assay with two strains which showed that these dimer analogues at 1, 2 x MIC were rapidly bactericidal and reduced the initial inoculum significantly during the first 2-6 h. Notably, dimer peptides showed synergy and additivity effects when used in combination with conventional antibiotics rifampin or penicillin respectively against the multidrug-resistant strains. In the Escherichia coli-infected mouse model, all of hybrid dimer analogues had significantly lower degree of bacterial load than the untreated control group when injected once i.p. at 5 mg/kg. In addition, the infected mice by methicillin-resistant (MRSA) strain could be effectively treated with J-RR. All of dimer analogues had membrane-active action mode. And the membrane-dependent mode of action signifies that peptides functions freely and without regard to conventional resistant mechanisms. Circular dichroism analyses of all dimer analogues showed a general predominance of a-helix conformation in 50% trifluoroethanol (TFE). Additionally, the acute toxicities study indicated that J-RR or J-AR did not show the signs of toxicity when adult mice exposed to concentration up to 120 mg/kg. The 50% lethal dose (LD50) off-AA was 53.6 mg/kg. In conclusion, to design and synthesize side chain-hybrid dimer analogues via click chemistry may offer a new strategy for antibacterial therapeutic option. (C) 2016 Elsevier Inc. All rights reserved.