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来至官网：http://www.oncorebiopharma.com/products/
ONCORE BIOPHARMA, INC.
TEKMIRA
topography.jpg
OnCore Biopharma, Inc. is Making a Difference
PRODUCTS & TECHNOLOGY
Goals of Hepatitis B Treatment
Aggressive suppression of HBV replication
Stimulation and reactivation of the suppressed immune response to HBV
Formation inhibition and elimination of cccDNA
Most companies in HBV research and development are applying different mechanisms to reduce viral load or boost the body's immune system to fight the disease. This will lead them to an "apparent virological cure".
LEARN MORE ABOUT WHAT THE EXPERTS THINK
Our Strategy
OnCore believes that eradicating covalently closed circular DNA (cccDNA) in HBV-infected hepatocytes represents the most important component for a combination cure of chronic hepatitis B. OnCore is currently developing an all-oral, permanent HBV cure by targeting cccDNA.
OnCore is combining agents against cccDNA with other potentially novel direct acting antiviral mechanisms and strategies that engage host immune response. OnCore believes that combination therapy will be required to achieve complete eradication of HBV from the liver.
The hepatitis B virus replicates primarily in the liver and deposits in the nucleus of liver cells a reservoir of stable viral genomic material called covalently closed circular DNA (cccDNA) that ultimately leads to the production of more virus. cccDNA also leads to the production of viral protein and genomic materials that are known to negatively impact the host immune response to the viral infection by preventing a credible anti-viral immune response. Consequently, viral replication leads to compromised liver function and damage. OnCore’s strategy is to take a combination approach toward an HBV cure: aggressively suppress HBV replication within liver cells, stimulate and reactivate the body's immune system so that it can mount an effective defense against the virus and, most importantly, eliminate cccDNA from infected cells.
Our Technologies
Inhibition of HBV viral replication has historically been achieved in a limited way by nucleoside and nucleotide viral polymerase inhibitors. These agents have been able to dramatically reduce viral load, however, they lack the ability to completely suppress viral replication and have virtually no effect on the sustained suppression of HBsAg or HBeAg levels. These therapies do not address the fundamental problem of cccDNA persistence. Consequently, we believe that targeting multiple points in the viral replication process is critical to effect a cure. We are developing a portfolio that includes molecules and intellectual property that address cccDNA and viral replication. In addition, OnCore is evaluating several approaches for stimulation and reactivation of the host immune response.
cccDNA
Infection of a hepatocyte leads to the importation of HBV relaxed circular DNA (rcDNA) into the cell nucleus. This rcDNA is converted to cccDNA by host enzymes forming a stable epichromasome. cccDNA is the source of genomic material and HBV persistence within the liver. OnCore believes that inhibition of cccDNA formation or transcriptional control, together with liver cell turnover, is central to HBV eradication.
OnCore is developing strategies to inhibit formation and control transcription of HBV cccDNA.
Capsid Assembly
cccDNA transcription produces HBV pregenomic RNA (pgRNA), to which is covalently bound the HBV viral polymerase. This complex must be encapsidated by a sphere of viral capsid proteins to continue the viral lifecycle, producing more virus particles and enabling the replenishment of cccDNA in the nucleus of hepatocytes. Inhibiting pgRNA encapsidation effectively terminates the progression of the virus lifecycle and inhibits viral replication.
OnCore is developing viral capsid assembly inhibitors to inhibit viral replication via a mechanism of action that can be used in combination with other direct acting antiviral agents and host immune modulators under development.
Cyclophilins
Cyclophilins are a class of proteins that have been implicated in the control of the innate immune response following viral infection. It is believed that interference of the interaction of cyclophilins with the interferon signaling pathway is one mechanism by which viruses are able to take control of the host innate immune response. Inhibitors of cylcophilins have been shown to be clinically effective at reducing viral load in patients infected with the hepatitis C virus. Viral control of cyclophilin-mediated immune response has also been implicated in HBV infection.
OnCore is investigating cyclophilin inhibitors as anti-HBV immunostimulatory agents with the objective of combining a potent cyclophilin inhibitor and direct acting antiviral agents to eradicate HBV. OnCore's initial drug candidate is OCB-030.
OCB-030 is an orally available, sangamide-based, second generation cyclophilin inhibitor with a well-differentiated preclinical profile when compared to other cyclophilin inhibitors. Data presented in April at The International Liver Congress™ 2014, the annual meeting of the European Association for the Study of the Liver (EASL), indicated that OCB-030 may inhibit the hepatitis B virus by two mechanisms in vitro. First, the data indicated that OCB-030 directly inhibits several stages of viral replication in liver cells. Second, the data indicated that OCB-030 may act indirectly by strengthening the host immune response via IRFs, including potent inhibition of an interaction between cyclophilin A and IRF9, a key component of the Jak/Stat pathway. Data also indicated that the risk of developing resistance, a significant clinical problem with current therapies for hepatitis B, is very low with OCB-030.
Surface Antigen
HBV surface antigen (HBsAg) is one of the viral proteins that plays an essential role in controlling the host immune response. HBsAg exists in large quantities not only as a constituent of HBV virions but also in HBV subviral particles, which significantly outnumber infectious virions circulating in the body. HBsAg has been shown to inhibit the innate immune response through effects on T-cell and dendritic cell function. The inhibition of HBsAg production or secretion holds the promise of reducing the impact of the viral infection on host immune function.
OnCore's program in the inhibition of HBsAg secretion is directed at helping to reactivate the immune system to combat viral infection.
谷歌翻译下产品与技术
乙肝治疗的目标
HBV复制的进取抑制
刺激到乙肝病毒的抑制免疫反应和激活
形成抑制和消除的cccDNA的
大多数公司在乙肝病毒的研究和开发应用不同的机制，以减少病毒载量或提高人体的免疫系统抗击疾病。这将导致他们的“明显的病毒学治愈”。
了解更多有关的专家认为
我们的策略
OnCore认为，在乙肝病毒感染的肝细胞消灭共价闭合环状DNA（cccDNA的）代表慢性乙型肝炎OnCore的组合治疗中最重要的组成部分，目前由目标开发的cccDNA全口服，永久乙肝治愈。
OnCore是结合药物对cccDNA的具有从事宿主免疫反应等潜在的新的直接作用的抗病毒机制和战略。 OnCore认为组合疗法将需要实现完全根除的HBV从肝脏。
乙肝病毒复制主要在肝细胞中的核的称为共价闭合环状DNA（cccDNA的）稳定病毒基因组物质的贮最终导致产生更多的病毒的肝脏和沉积物。的cccDNA也导致产生的已知会通过防止一个可信的抗病毒免疫应答的宿主的免疫反应造成负面影响的病毒感染的病毒蛋白和基因组材料。因此，病毒复制会导致损害肝功能和损坏。 OnCore的策略是采取相结合的方式对一个乙肝病毒治疗：肝细胞内积极地抑制HBV的复制，刺激并激活人体的免疫系统，使之能够最重要的挂载对抗病毒，有效的防御，消除cccDNA的从感染细胞。
我们的技术
HBV病毒复制的抑制历来以有限的方式取得由核苷和核苷酸病毒聚合酶抑制剂。这些药物已能显着降低病毒载量，然而，它们缺乏完全抑制病毒复制的能力，并具有对HBsAg或HBeAg的水平的持续抑制几乎没有影响。这些疗法没有解决的cccDNA持久性的根本问题。因此，我们认为，在病毒复制过程中靶向多个点是关键的，以实现治愈。我们正在开发一个组合，包括分子和知识产权，解决的cccDNA与病毒复制。此外，OnCore正在评估几种方法用于刺激宿主免疫应答的和再活化。
cccDNA的
肝细胞的感染导致HBV松弛环状DNA（rcDNA）进口到细胞核内。这rcDNA被宿主酶形成稳定epichromasome转换为cccDNA的。 cccDNA的是肝脏内基因组材料和HBV的持久性的来源。 OnCore认为，抑制cccDNA的形成或转录调控，肝细胞的营业额在一起，是中央对乙肝病毒消灭。
OnCore发展战略，以抑制HBV的cccDNA的形成和控制转录。
衣壳包装
cccDNA的转录产生HBV的前基因组RNA（pgRNA）中，向其中共价结合的HBV病毒聚合酶。这种复杂的，必须由病毒衣壳蛋白的一个球体被包被以继续病毒的生命周期，产生更多的病毒粒子和有利的cccDNA的补充肝细胞的细胞核中。抑制pgRNA衣壳化有效终止病毒生命周期的恶化，并抑制病毒复制。
OnCore正在开发的病毒衣壳组装抑制剂经由动作的，可用于结合其它直接作用的抗病毒剂和正在开发的宿主免疫调节剂的一种机制，以抑制病毒复制。
亲环素
亲环是一类蛋白质，它们有牵连下列病毒感染的先天免疫反应的控制。据信亲环与干扰素信号传导途径的相互作用的干扰是一种机制通过该病毒是能够利用宿主先天免疫反应的控制。 cylcophilins的抑制剂已被证明是临床上有效的减少患者感染了丙型肝炎病毒的病毒载量。的亲环介导的免疫应答的病毒控制也被牵连于HBV感染。
OnCore正在调查亲环蛋白抑制剂是抗HBV免疫刺激剂相结合的有力亲环素抑制剂的目标，并直接作用抗病毒药物，以消除乙肝病毒。 OnCore最初的候选药物是OCB-030。
OCB-030是可口服的，sangamide为主，第二代环素抑制剂与分化良好的临床前轮廓相对于其他亲环蛋白抑制剂。在国际肝病会议™2014年，欧洲协会为肝脏（EASL）的研究的年度会议上提出在4月份的数据，表明OCB-030可以通过体外两种机制抑制乙肝病毒。首先，数据表明，OCB-030直接抑制病毒复制的数个阶段中的肝细胞。第二，数据表明，OCB-030可间接通过加强经由脉冲响应函数宿主的免疫反应，包括亲环素A和IRF9中，JAK / STAT途径的一个关键组成部分之间的相互作用的强效抑制起作用。数据还表明，显影耐药的风险，一个显著临床问题目前疗法为乙型肝炎，非常低，OCB-030。
表面抗原
乙肝病毒表面抗原（HBsAg）是病毒蛋白质，在控制宿主的免疫反应中起重要作用的一个。 HBsAg的存在大量不仅作为乙肝病毒粒子的构成成分，而且在HBV亚病毒颗粒，其显著多于感染性病毒粒子在体内循环。的HBsAg已经显示出抑制通过T细胞和树突状细胞的功能效应的先天免疫应答。乙肝表面抗原产生或分泌的抑制作用持有减少病毒感染对机体免疫功能的影响的承诺。
OnCore在的HBsAg分泌的抑制方案是针对帮助重新激活免疫系统对抗病毒感染。
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发表于 2015-10-2 10:27
