首页 > 检验医学 >  EASL2017:Contravir公司在研乙肝新药CRV431和CMX157联合或具治愈慢乙肝潜力

EASL2017:Contravir公司在研乙肝新药CRV431和CMX157联合或具治愈慢乙肝潜力

2017-04-25  来源:肝脏巴士(HeparBus)微信  作者:无聊的猫  编辑:放下
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据认为,治愈慢乙肝的方法将会是要求两种或多种药物联合的方案,通过不同药物作用于乙肝病毒的复制和繁殖的不同阶段。Contravir 公司的替诺福韦(TFV)前药CMX157是一
 
据认为,治愈慢乙肝的方法将会是要求两种或多种药物联合的方案,通过不同药物作用于乙肝病毒的复制和繁殖的不同阶段。Contravir 公司的替诺福韦(TFV)前药CMX157是一种新型脂质无环核苷(NUC)膦酸盐,旨在希望能够靶向提高肝内TFV浓度,而又能降低血液循环中的浓度进而最小化非靶向器官的损伤。CRV431也是Contravir 公司的一款在研乙肝新药,目前正处于早期开发阶段,其靶向抑制亲环素(亲环素A[cypA],一种肽基脯氨酰异构酶)从而具有抗病毒作用。一旦cypA受到抑制,CRV431 就能限制 HBV DNA, 抑制HBsAg,通过NTCP抑制病毒摄取,最近的研究发现其具有阻碍HBx-cypA结合作用。Contravir 公司在此次2017欧洲肝病学会年会上公布了CMX157联合CRV431对HBV DNA的影响。
 
该研究测量了 CRV431 单药 0至320nM 范围内以及跟CMX157(浓度范围 0至640nM )联合用药对细胞内 HBV DNA 的抑制情况。两组试验均在AD38,DE19和DES19细胞系的体外环境中进行测试。每个研究分别进行两次,一式三份,使用DMSO作为对照。使用Prichard-Shipman MacSynergy评估药物浓度与效应。另外,在许多原代人细胞和细胞系中检查了CRV431的细胞毒性,分别利用DMSO和0.5%皂角苷作阴性和阳性对照,比较环孢菌素,alisporivir 和 sanglifehrin A 以证实测定中的细胞活力。
  
在三种细胞类型中测试的 CRV431 联合 CMX157 用药,细胞内 HBV DNA 受抑制表现出低纳摩尔范围的IC50值。CRV431 与 CMX157 的协同评分显示两者具有中等至强力的协同作用。此外,在所有CRV431浓度中测试的细胞都是具有活性的,超过了alisporivir,环孢菌素的生存力,并且远远超过 sanglifehrin A。CRV431显示出约24μM的CC50值。选择性指数(SI)与alisporivir,环孢菌素和sanglifehrin A 相比,CRV431最广。
 
CRV431和CMX157的联合代表了治愈HBV的可行治疗药物策略。该策略利用了两种药物的互补作用机制,可以抑制HBV DNA,HBsAg,HBeAg,抑制病毒进入,阻断cypclophilin A结合HBx。CRV431与CMX157的互补作用或可以合理地扩展到具有其他活性形式的药物,例如核心抑制剂。

 
编号:SAT-180
 
CRV431 and CMX157: anti-HBV combination effects in vitro between a cyclophilin inhibitor and a nucleotide prodrug
 
R.T. Foster1, D.J. Trepanier1, D.R. Ure1, J. Greytok1, J.L. Kulp2, P. Gallay3.1Contravir Pharmaceuticals Inc., Edison; 2Baruch S Blumberg Institute,Doylestown; 3The Scripps Research Institute, San Diego, United States
 
E-mail: rfoster@contravir.com
 
Background and Aims: It is expected that a cure for HBV will require drug combinations that interact at more than one stage of viral replication and propagation. Our lead drug, CMX157, a tenofovir (TFV)prodrug, is a novel lipid acyclic nucleoside (NUC) phosphonate designed to deliver high intrahepatic concentrations of TFV, while minimizing off-target effects caused by high levels of circulating TFV.CRV431, our earlier-stage molecule, is a host targeting antiviral that inhibits cyclophilins, namely cyclophilin A (cypA), a peptidyl prolyl isomerase. As a cypA inhibitor, CRV431 reduces HBV DNA, suppresses HBsAg, inhibits viral uptake via NTCP and, more recently, has been shown to impede HBx-cypA binding. The aim of the current study was to investigate the combination of CMX157 and CRV431,measuring HBV DNA.
 
Methods: The current study measured inhibition of intracellular HBV DNA at concentrations of CRV431 ranging from 0 to 320 nM alone,and in combination with CMX157 ranging from 0 to 640 nM. Both drugs were tested in vitro in AD38, DE19, and DES19 cells. Studies were each conducted twice, in triplicate, using DMSO as control. Drug concentration versus effect was evaluated using Prichard-Shipman MacSynergy. Additionally, CRV431 cytotoxicity was examined in a number of primary human cells and cell lines, utilizing DMSO and 0.5% saponin as negative and positive controls, respectively, comparing cyclosporine, alisporivir, and sanglifehrin A, to confirm cell viability in the assays.
 
Results: Intracellular HBV DNA inhibition with CRV431 and CMX157,tested in combination with all three cell types, exhibited IC50 values in the lownanomolar range. Synergy scores for CRV431 with CMX157 indicated moderate to strong synergy. Further, cells were viable across all CRV431 concentrations tested, exceeding the viability of alisporivir, cyclosporine, and far exceeding sanglifehrin A. CRV431 exhibited CC50 values of approximately 24 μM. The selective index (SI) was widest for CRV431 compared with that of alisporivir, cyclosporine, and sanglifehrin A.
 
Conclusions: CRV431 and CMX157, tested in combination, represents a viable therapeutic drug strategy for the cure of HBV. This strategy exploits the complementary modes of action of the two drugs, which allows for suppression of HBV DNA, HBsAg, HBeAg, inhibition of viral entry, and blocking of cypclophilin A binding to HBx. The complementary actions of CRV431 with CMX157 may reasonably extend to drugs with other modes of activity including, for example, core inhibitors.
 
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