Enhancement of Antiviral Activity of Human Alpha-Defensin 5 against Herpes Simplex Virus 2 by Arginine Mutagenesis at Adaptive Evolution Sites
Enhancement of Antiviral Activity of Human Alpha-Defensin 5 against Herpes Simplex Virus 2 by Arginine Mutagenesis at Adaptive Evolution Sites
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通过适应性进化位点的精氨酸诱变增强人α-防御素 5 对单纯疱疹病毒 2 的抗病毒活性
DOI：
10.1128/jvi.02209-12
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
Wang, Junping
中科院分区：
文献类型：
--
作者：
Ran, Xinze;Su, Yongping;Cheng, Tianmin;Wang, Junping
ABSTRACT Herpes simplex virus 2 (HSV-2) infection is still one of the common causes of sexually transmitted diseases worldwide. The prevalence of HSV strains resistant to traditional nucleoside antiviral agents has led to the development of novel antiviral drugs. Human alpha-defensin 5 (HD5), a kind of endogenous antimicrobial peptide expressed in the epithelia of the small intestine and urogenital tract, displays natural antiviral activity. Based on arginine-rich features and adaptive evolution characteristics of vertebrate defensins, we conducted a screen for HD5 derivatives with enhanced anti-HSV-2 activity by a single arginine substitution at the adaptive evolution sites. Cell protection assay and temporal antiviral studies showed that HD5 and its mutants displayed affirmatory but differential anti-HSV-2 effects in vitro by inhibiting viral adhesion and entry. Inspiringly, the E21R-HD5 mutant had significantly higher antiviral activity than natural HD5, which is possibly attributed to the stronger binding affinity of the E21R-HD5 mutant with HSV-2 capsid protein gD, indicating that E21R mutation can increase the anti-HSV-2 potency of HD5. In a mouse model of lethal HSV-2 infection, prophylactic and/or therapeutic treatment with E21R-HD5 via intravaginal instillation remarkably alleviated the symptoms and delayed disease progress and resulted in about a 1.5-fold-higher survival rate than in the HD5 group. Furthermore, the E21R variant exhibited a 2-fold-higher antiviral potency against HIV-1 over parental HD5 in vitro. This study demonstrates that arginine mutagenesis at appropriate evolution sites may significantly enhance the antiviral activity of HD5, which also paves a facile way to search for potent antiviral drugs based on natural antimicrobial peptides.
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影响因子：
2.2
作者：
Theresa L. Chang;M. Klotman
通讯作者：
Theresa L. Chang;M. Klotman
影响因子：
4.4
作者：
Lehrer, Robert I.;Jung, Grace;Lu, Wuyuan
通讯作者：
Lu, Wuyuan
影响因子：
10.7
作者：
D. Lynn;A. Lloyd;M. Fares;C. O’Farrelly
通讯作者：
D. Lynn;A. Lloyd;M. Fares;C. O’Farrelly
DOI：
--
发表时间：
2006
影响因子：
11.1
作者：
C. Buck;P. Day;C. Thompson;J. Lubkowski;Wuyuan Lu;D. Lowy;J. Schiller
通讯作者：
C. Buck;P. Day;C. Thompson;J. Lubkowski;Wuyuan Lu;D. Lowy;J. Schiller
影响因子：
4.8
作者：
Cao Xie;A. Prahl;Bryan Ericksen;Zhibin Wu;Pengyun Zeng;Xiangqun Li;Weiyue Lu;J. Lubkowski;
通讯作者：
Cao Xie;A. Prahl;Bryan Ericksen;Zhibin Wu;Pengyun Zeng;Xiangqun Li;Weiyue Lu;J. Lubkowski;