SCY-635: Cyclophilin inhibitor亲环素抑制剂

StephenW

Scynexis' Oral SCY-635 Shows Potential
From the PharmaLive.com News Archive - Nov. 11, 2012
Scynexis announced the results of a Phase 2a study of lead candidate SCY-635 in combination with pegylated interferon and ribavirin (Peg-IFN/RBV) for the treatment of the hepatitis C virus that showed SCY-635 has the potential to play an important role in the reversal of immune exhaustion, restoring the immune systems of difficult to treat patients with HCV.
Scynexis英语口语SCY-635显示了潜在的
从该PharmaLive.com的新闻存档 -  2012年11月11日
Scynexis宣布的结果2A期研究的主角人选SCY-635结合聚乙二醇干扰素和利巴韦林治疗的丙型肝炎病毒（Peg-IFN/RBV）表明SCY-635有可能发挥了重要的作用在逆转的免疫耗竭，恢复难以治疗HCV患者的免疫系统。
关于SCY-635
About SCY-635

SCY-635 is a novel oral Cyclophilin inhibitor in Phase 2 studies for the treatment for Hepatitis C (HCV) and in preclinical studies for the treatment of Hepatitis B (HBV). Studies to date have demonstrated that SCY-635 is unique in that it plays a dual role as a synergistic Direct Acting Antiviral (DAA) and a stimulator of the host immune system (Immune Acting Antiviral or IAA). The addition of SCY-635 to the repertoire of currently approved HCV therapies could breathe new life into the future of the immunotherapeutic options for treating HCV.
SCY-635是一种新型的口服亲环素抑制剂在第二阶段研究用于治疗丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）治疗的临床前研究。最新研究表明，SCY-635的独特之处在于它扮演着双重角色，作为一个协同的直接作用抗病毒药物（DAA）和刺激宿主的免疫系统（免疫代理抗病毒药物或IAA）。 SCY-635的剧目目前已获得批准的HCV疗法可以用于治疗丙型肝炎的免疫治疗方案的未来注入新的活力。

StephenW

EASL 2012
PROGRAM ABSTACT

ALISPORIVIR-INDUCED INHIBITION OF CELLULAR CYCLOPHILINS DISRUPTS HEPATITIS B VIRUS (HBV) REPLICATION IN VITRO AND IS SYNERGISTIC IN COMBINATION WITH DIRECT ANTIVIRAL TARGETING HBV-DNA POLYMERASE

Speaker: Shilpa Chokshi Author: S. Phillips1, S. Chokshi1*, A. Riva1, N.V. Naoumov2 Affiliation: 1Foundation for Liver Research, Institute of Hepatology, London, UK, 2Novartis Pharma AG, Basel, Switzerland. *[email protected]

Background/aims: Cyclophilins are intracellular proteins with enzymatic activity - peptidyl-prolyl-isomerase that plays a major role in the life cycle of Hepatitis C virus. By targeting host cyclophilins Alisporivir (DEB025) exerts potent anti-HCV activity in vitro and in clinical studies. We have recently shown in vitro that cyclophilin inhibition with Alisporivir or NIM811 also interferes with HBV replication, with Alisporivir having a greater effect than NIM811. To elucidate the underlying mechanisms, in the present study we compared in vitro the effects on HBV replication of Alisporivir alone, Alisporivir in combination with a potent antiviral targeting HBV-DNA polymerase, and in cells after selective knockdown of individual cyclophilins.

Material and methods: Stably(HepG2215) and transiently(HUH-7) transfected cells, producing full HBV virions and HBsAg particles, were treated with a range of Alisporivir concentrations (0.25/1.0/5.0/20 ug/ml) alone, Telbivudine alone, or combinations of Alisporivir and Telbivudine. To determine the involvement of individual cyclophilins, HepG2215 cells were transfected with siRNA-specific for cyclophilin (Cyp) A, C or D and additionally treated with Alisporivir. Cytoplasmic extracts and supernatants were harvested at baseline; 24, 48 and 72 hours post-treatment. The kinetics of antiviral activity was assessed by quantitation of intracellular and secreted HBV-DNA (real-time qPCR) and HBsAg levels (ELISA).

Results: Both in HepG2215 and HUH-7 cells, Alisporivir treatment resulted in dose-dependent reduction of intracellular and secreted HBV-DNA at all time points, by 70% (p=0.004) and 63% (p< 0.001), respectively, compared with untreated controls. The combination of Alisporivir and Telbivudine had greater effects in reducing intracellular (p=0.001) and secreted (p=0.028) HBV-DNA, and >3-fold reduction of HBsAg versus either Alisporivir or Telbivudine alone. CypA, C or D expression was markedly reduced after transfection with corresponding siRNA, which was associated with significant decrease of HBV-DNA and HBsAg levels (p< 0.001). Alisporivir treatment of cells silenced for CypA, C or D further reduced HBV-DNA and HBsAg levels, with greater antiviral effects in CypC or CypD silenced cells, compared with CypA silenced cells (p< 0.001).

Conclusion: These results suggest that Alisporivir interferes with multiple sites of HBV replication and its antiviral activity is synergistic with direct antiviral targeting viral DNA polymerase, such as Telbivudine.

细胞的ALISPORIVIR抑制亲环素会破坏乙型肝炎病毒（HBV）复制的体外培养和直接抗病毒靶向HBV-DNA聚合酶结合是协同

主讲人：希尔帕Chokshi作者：S. S. Chokshi1 Phillips1，*，A. Riva1，NV Naoumov2的单位：1Foundation的肝病研究学会的杂​​志，伦敦，英国，瑞士巴塞尔的制药公司，2Novartis。 * s.chokshi @ researchinliver.org.uk

背景/目的：亲环素是细胞内酶的活性蛋白 - 肽基脯氨酰异构酶，C型肝炎病毒的生命周期中起着重要的作用。通过针对主机：亲环Alisporivir（DEB025）施加在体外和在临床研究中的有效的抗-HCV活性。最近，我们已经证明在体外，环素抑制与Alisporivir或NIM811的干扰HBV复制，，与Alisporivir有更大的影响比NIM811。为了阐明的基本机制，在本研究中，我们比较了在体外对HBV复制的Alisporivir单独，Alisporivir在一种有效的抗病毒靶向HBV-DNA聚合酶结合，并在细胞后选择性击倒的个别的亲环素的影响。

材料与方法：可以稳定（HepG2215）和瞬时转染细胞（HUH-7），完整的HBV病毒颗粒和HBsAg颗粒，分别用一个单独的Alisporivir浓度范围内（0.25/1.0/5.0/20微克/毫升），替比夫定单独或的Alisporivir和替比夫定的组合。要确定参与的个人亲环素，HepG2215细胞转染siRNA的特定亲环素（CYP）A，C或D另外处理Alisporivir。细胞质提取物，收集上清液在基线，24小时，48小时和72小时后处理。抗病毒活性的动力学是由细胞内和细胞分泌的HBV-DNA（实时定量PCR）和HBsAg的水平（ELISA）定量评估。

结果：在HepG2215和Huh-7细胞，Alisporivir治疗导致剂量依赖性降低细胞内和细胞分泌HBV-DNA在所有时间点，70％（P = 0.004）和63％（P <0.001），分别与未处理的对照组相比。相结合，Alisporivir和替比夫定（P = 0.001），降低细胞内和分泌有较大影响（P = 0.028），HBV  -  DNA，和乙肝表面抗原与Alisporivir或替比夫定单独的3倍减少。 CypA基因，C或D的表达显着降低，与相应的siRNA转染后，与HBV-DNA和HBsAg水平（P <0.001）显着减少。 CypA基因，C或D沉默的细胞Alisporivir治疗进一步降低HBV-DNA和HBsAg水平，在CypC或CypD沉默的细胞具有更大的抗病毒效果，CypA基因沉默的细胞（P <0.001）。

结论：这些结果表明，Alisporivir干扰HBV复制的多个站点，其抗病毒活性具有直接抗病毒的靶向病毒DNA聚合酶，如替比夫定是协同。

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