The lantibiotic peptide labyrinthopeptin A1 demonstrates broad anti-HIV and anti-HSV activity with potential for microbicidal applications.
The lantibiotic peptide labyrinthopeptin A1 demonstrates broad anti-HIV and anti-HSV activity with potential for microbicidal applications.
复制标题
DOI：
10.1371/journal.pone.0064010
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Schols D
中科院分区：
文献类型：
--
作者：
Férir G;Petrova MI;Andrei G;Huskens D;Hoorelbeke B;Snoeck R;Vanderleyden J;Balzarini J;Bartoschek S;Brönstrup M;Süssmuth RD;Schols D
羊毛硫抗生素是由细菌产生的肽，含有非规范氨基酸羊毛硫氨酸，其中许多具有抗菌活性。迷路肽A1（LabyA 1）是一类新型碳环羊毛硫抗生素的原型肽。在这里，我们广泛地评估了其对HIV和HSV的体外广谱活性，研究了其作用机制，并评估了潜在的杀微生物应用。LabyA 1在细胞培养物中表现出一致和广泛的抗HIV活性（EC 50：0.70-3.3 µM）和抗HSV活性（EC 50：0.29-2.8 µM）。LabyA 1还可抑制持续HIV感染的T细胞和未感染的CD 4 + T细胞之间的病毒细胞间传播（EC 50 ∶2.5 µM），并抑制DC-SIGN+-细胞捕获的HIV向未感染的CD 4 + T细胞的传播（EC 50 ∶4.1 µM）。药物添加时间研究表明，LabyA 1可作为HIV和HSV的进入抑制剂。结合SPR/FLIPR技术的细胞和病毒结合研究表明，LabyA 1与HIV包膜蛋白gp 120相互作用，但不与HIV细胞受体相互作用。LabyA 1还证明了其抗HIV-1和抗HSV-2活性与抗（逆转录）病毒药物双重组合的加和协同效应，如替诺福韦，阿昔洛韦，沙奎那韦，雷特格韦和恩夫韦肽。LabyA 1对HIV和HSV具有显著的抗病毒活性，可被认为是一种新型的先导肽。用LabyA 1预处理PBMC既不增加活化标志物CD 69和CD 25的表达，也不增强HIV复制，也不显著诱导各种炎性细胞因子/趋化因子。LabyA 1也不影响阴道乳酸杆菌种群的生长。基于对阴道乳杆菌属菌株的毒性的缺乏及其与临床批准的抗（逆转录）病毒药物组合的协同/相加特性，其作为预防性传播疾病的潜在杀微生物剂候选物值得进一步关注。
Lantibiotics are peptides, produced by bacteria, that contain the noncanonical amino acid lanthionine and many of them exhibit antibacterial activities. The labyrinthopeptin A1 (LabyA1) is a prototype peptide of a novel class of carbacyclic lantibiotics. Here, we extensively evaluated its broad-spectrum activity against HIV and HSV in vitro, studied its mechanism of action and evaluated potential microbicidal applications. LabyA1 exhibited a consistent and broad anti-HIV activity (EC50s: 0.70–3.3 µM) and anti-HSV activity (EC50s: 0.29–2.8 µM) in cell cultures. LabyA1 also inhibited viral cell-cell transmission between persistently HIV-infected T cells and uninfected CD4+ T cells (EC50∶2.5 µM) and inhibited the transmission of HIV captured by DC-SIGN+-cells to uninfected CD4+ T cells (EC50∶4.1 µM). Time-of-drug addition studies revealed that LabyA1 acts as an entry inhibitor against HIV and HSV. Cellular and virus binding studies combined with SPR/FLIPR technology showed that LabyA1 interacted with the HIV envelope protein gp120, but not with the HIV cellular receptors. LabyA1 also demonstrated additive to synergistic effects in its anti-HIV-1 and anti-HSV-2 activity with anti(retro)viral drugs in dual combinations such as tenofovir, acyclovir, saquinavir, raltegravir and enfuvirtide. LabyA1 can be considered as a novel lead peptide as it had profound antiviral activity against HIV and HSV. Pre-treatment of PBMCs with LabyA1 neither increased the expression of the activation markers CD69 and CD25, nor enhanced HIV replication, nor significantly induced various inflammatory cytokines/chemokines. LabyA1 also did not affect the growth of vaginal Lactobacilli populations. Based on the lack of toxicity on the vaginal Lactobacillus strains and its synergistic/additive profile in combination with clinically approved anti(retro)virals, it deserves further attention as a potential microbicide candidate in the prevention of sexual transmitted diseases.
登录
查看更多内容
影响因子：
5.4
作者：
DeVreese, K;KoflerMongold, V;Werner, G
通讯作者：
Werner, G
影响因子：
14.8
作者：
Daelemans D;Pauwels R;De Clercq E;Pannecouque C
通讯作者：
Pannecouque C
影响因子：
3.7
作者：
Goethals, Olivia;Vos, Ann;Clayton, Reginald
通讯作者：
Clayton, Reginald
影响因子：
2.4
作者：
Choi, MH;Park, YH
通讯作者：
Park, YH
影响因子：
7.6
作者：
Chono, Koji;Katsumata, Kiyomitsu;Shiraki, Kimiyasu
通讯作者：
Shiraki, Kimiyasu