SALP - INHIBITING HEPATITIS B VIRUS ENTRY BY PREVENTING VIRUS INTERACTION WITH T

StephenW

Oral Presentations    Session Title: Parallel Session:HEPATITIS B
Presentation Date: 01 APR, 2011
NOVEL PEPTIDE-BASED MICROBIOCIDES
http://www1.easl.eu/easl2011/program/Orals/338.htm
INHIBITING HEPATITIS B VIRUS ENTRY BY PREVENTING VIRUS INTERACTION WITH THE CELL SURFACE

J. Lucifora1*, I. Kowalski2, Y. Xia1, K. Brandenburg2, U. Protzer1
1Institute of Virology, Technische Universität München / Helmholtz Zentrum München, Munich, 2Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Naturwissenschaften, Borstel, Germany. *[email protected]

Background and aims: Current treatment regimens usually fail to cure chronically HBV-infected patients. Most approved therapies are targeting the viral polymerase activity without preventing virus entry and formation of the very stable HBV transcription template, leading to viral rebound after treatment arrest or to development of viral resistance in case of prolonged treatment. Development of entry inhibitors is thus very important and will improve therapeutic options but also prevent vertical transmission and reinfection after liver transplantation or serve as post-exposure prophylaxis.
Methods: Synthetic anti-lipopolysaccharide peptides (SALP) were designed, synthesized and tested for their antiviral effect using HBV-infected HepaRG cells.
Results: We showed that polycationic amphiphilic SALP very efficiently and dose dependently inhibit HBV infection if cells are treated prior and during infection. All the HBV markers (including cccDNA, HBV-RNA, HBeAg, HBsAg, intracellular rc-DNA) were reduced from 50% between the concentration ranges of 0.5 to 2 µg/mL and from 90% between 4 to 5 µg/mL without any toxicity observed. No effect was seen in cells treated after HBV infection. Using different peptides, we showed that overall positive charges and their equal distribution over the peptide, rather than the sequence or the hydrophobicity of the peptides, seem to determine entry inhibition. By heparin affinity chromatography of HBV particles in presence of SALP we observed that HBV particles binding to heparin was 60 % reduced, suggesting that SALP compete with HBV for binding to heparin.
Conclusions: Altogether, our results demonstrated that SALP inhibit initial binding of HBV to the cell surface by direct interaction to heparan sulfate. In parallel, SALP were demonstrated to be also active against e.g. HIV or herpes viruses and to exhibit broad antimicrobial potential in mice models of peritonitis, colitis, and pneumonia. Thus, SALP represent a very promising therapeutic strategy to treat virus infection with concomitant bacterial infection that often lead to life-threatening systemic complications such peritonitis accompanying HBV- or HCV-related liver cirrhosis.

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StephenW

口头报告

会议名称：平行会议：乙型肝炎
颁奖日期：2011年4月1日
新型肽基杀微生物抑制乙型肝炎防止病毒与细胞表面相互作用病毒入境

j的Lucifora 1 *，一科瓦尔斯基2，华霞1，光勃兰登堡2，美国Protzer 1
病毒学，慕尼黑工业大学/亥姆霍兹慕尼黑，慕尼黑，2Forschungszentrum博斯特尔，莱布尼茨- Zentrum酒店献给Medizin 1中国科学院有限公司Naturwissenschaften，博斯特尔，德国。 * [email protected]

背景与目的：目前的治疗方案通常无法治愈慢性乙肝病毒感染的病人。多数批准疗法的目标是把没有阻止病毒侵入和非常稳定的乙肝病毒聚合酶转录模板形成的活性，从而在长期治疗的情况下逮捕治疗后病毒反弹或病毒抗药性的发展。进入抑制剂的开发是非常重要的，从而将改善治疗方案，但还可以防止肝移植术后再感染或垂直传播和作为暴露后预防。
方法：合成抗内毒素肽（SALP）设计，合成和利用其抗病毒HBV感染HepaRG细胞的影响进行测试。
结果：我们发现，阳离子两亲SALP非常有效和剂量依赖性地抑制乙肝病毒感染的细胞，如果治疗前和期间感染。所有的乙肝病毒标志物（包括cccDNA的，乙肝病毒的RNA，e抗原，乙肝表面抗原，细胞内的第RC - DNA）的由50％减少至0.5至2微克的浓度范围/ mL和/毫升之间没有任何从90％，4至5微克毒性观察。没有效果在治疗后乙肝病毒感染的细胞。使用不同的肽，我们发现，总体正电荷和他们对肽，而不是序列或疏水性的肽平均分配，以确定项目似乎抑制。肝素亲和乙肝病毒颗粒存在于SALP层析我们观察到乙肝病毒颗粒结合肝素减少60％，这表明SALP乙肝竞争结合肝素。
结论：总之，我们的研究结果初步表明，SALP抑制乙肝病毒结合到细胞表面的直接接触硫酸乙酰肝素。与此同时，SALP被证明是对如还积极疱疹病毒和艾滋病毒或展示在腹膜炎，肠炎，肺炎小鼠模型广泛的抗菌潜力。因此，SALP代表一个非常有前途的治疗方法来治疗伴细菌感染，往往导致危及生命的全身性并发症，如腹膜炎伴随乙肝病毒或丙型肝炎病毒感染相关的肝硬化。

非东亚病夫

这么好的消息，为什么要在4月1日开发布会啊~！
搞得我心汗汗哦。

StephenW

非东亚病夫 发表于 2011-4-3 12:21
这么好的消息，为什么要在4月1日开发布会啊~！
搞得我心汗汗哦。

EASL 会议,3月30日至四月三号.

非东亚病夫

4月1日 是 愚人节 啊~！感觉怪怪~！