CPI-431-32 亲环蛋白抑制剂：一种新的，多功能类药物

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Cyclophilin Inhibitors: A New, Multifunctional Drug Class

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Ciclofilin Pharmaceuticals Inc. has developed a pipeline of novel, proprietary cyclophilin inhibitors (CPIs) using in-house expertise, which have the potential to treat a wide variety of diseases and disorders.

Cyclophilins are a family of evolutionarily conserved proteins that are found in most cells in the body. Their most recognized activity is enzymatic regulation of the cis-trans isomeric structure of peptidyl-proline bonds in target proteins.  Peptidyl-proline bonds are abundant in nature, and their isomeric conformation increasingly is being recognized as an important regulator of protein function (1).  As such, cyclophilin isomerases represent an important class of protein folding enzyme. Their involvement in protein maturation and trafficking also afford them classification as molecular chaperones. Some cyclophilin isoforms also are secreted by cells and act as chemokines or cytokines by binding and activating cell surface receptors, especially CD147.  CD147 activation commonly is involved in inflammatory events (2).  Through these interactions cyclophilins play roles in mitochondrial function, calcium homeostasis, oxidative stress, intracellular signaling, leukocyte trafficking, cellular responses to injury, and other processes (3).  Despite these prominent roles, studies indicate that genetic deletion or inhibition of individual cyclophilins do not seriously impact normal physiology.  Thus, cyclophilins appear to contribute to, but are not absolutely necessary for physiological stability under normal conditions.

In contrast, cyclophilins have been shown to play pivotal roles in many diseases and injury conditions by exacerbating pathological processes and propagating disease phenotypes (4).  For example, cyclophilin D activity promotes mitochondrial transition pore opening and mitochondria-mediated cell death in ischemia-reperfusion and other disorders involving oxidative stress and intracellular calcium overload.  In many inflammatory diseases, secreted cyclophilin causes excessive accumulation and activation of neutrophils, lymphocytes, and macrophages. Cyclophilin expression is upregulated in several types of cancer, which may assist in metastasis. In various types of liver disease cyclophilins participate in inflammation, fibrosis, and cell death (5). Conversely, cyclophilin inhibition is protective across a spectrum of experimental disease models, including those for heart attack, stroke, traumatic brain injury, multiple sclerosis, ALS, Alzheimers, atherosclerosis, asthma, and arthritis.  Thus, cyclophilins are attractive therapeutic targets for many diseases.


Cyclophilins in Infectious Diseases

Cyclophilins also play important roles in the life cycles of many viruses, bacteria, and other pathogens (6).  Viruses that hijack and utilize host cell cyclophilins to replicate and disseminate disease include hepatitis C virus (HCV), human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), and multiple coronaviruses (e.g. SARS).  HCV and HIV-1 are the viruses for which the roles of cyclophilins are best described (7).  In HCV infection, cyclophilin A is bound by the nonstructural protein, NS5A, which is necessary for viral replication. Proper NS5A function is dependent on cyclophilin A isomerase activity.  In HIV-1 infection, cyclophilin A binds to the viral capsid which appears to stabilize the capsid core, promote nuclear entry, and ultimately facilitate reverse transcription.  Cyclophilin binding by HIV-1 is also a mechanism used to evade immune recognition in infected macrophages.  Thus, cyclophilin inhibitors stand to be the next generation of broadly-acting antiviral agent for some of the most prevalent viral diseases of our time.


Ciclofilin Pharmaceuticals' CPI Compounds

Ciclofilin Pharmaceuticals' expertise in cyclosporin chemistry, the backbone of cyclophilin inhibitors, and comprehensive screening programs has led to the discovery of many proprietary compounds with high in vitro potency (low nanomolar) cyclophilin inhibition, low cytotoxicity, and excellent pharmacokinetic and pharmacodynamics properties.  In addition, the flexibility in our chemical platform means that the compounds are customizable to meet the needs of specific diseases.

CPI-431-32 is Ciclofilin Pharmaceuticals' lead medicinal candidate for difficult-to-treat hepatitis patients.  CPI-431-32 arose from several years of nonclinical testing, optimization, and third-party validation.  The compound potently inhibits HCV and HIV-1 in vitro, including simultaneous inhibition of these viruses in a coinfection model.  In contrast to many antivirals that directly target viruses (direct acting antivirals; DAAs), CPI-431-32 targets host cyclophilin and therefore has a high barrier to emergence of drug resistance.  CPI-431-32 also demonstrates an advantage in being highly potent towards all HCV genotypes, including genotype 3 (i.e., pangenotypic), unlike most HCV DAAs which show much less antiviral potency towards HCV genotype 3.  Ciclofilin Pharmaceuticals' extensive discovery and optimization programs have laid the groundwork for rapid advancement of its lead compound through preclinical toxicology testing and submission of an Investigation New Drug application.

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亲环蛋白抑制剂：一种新的，多功能类药物

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Ciclofilin制药公司已经开发出新颖的，专有的亲环蛋白抑制剂（消费物价指数）采用内部专业知识的管道，它具有治疗多种疾病和病症的可能性。

亲环是一个家族被发现在大多数细胞在体内是进化上保守的蛋白质。他们最认可的活动是肽脯氨酸债券靶蛋白的顺反异构体结构的酶调控。肽基脯氨酸债券是丰富性的，它们的异构体的构象日益被公认为蛋白质的功能（1）的重要调节器。正因为如此，亲环异构酶代表蛋白质折叠酶一类重要的。其蛋白质成熟和贩运的参与也负担不起分类为分子伴侣。一些亲环亚型也由细胞和充当趋化因子或细胞因子分泌的结合和活化的细胞表面受体，特别是CD147的。 CD147活化通常是参与炎性事件（2）。通过这些相互作​​用亲环中的线粒体功能，钙稳态，氧化应激，细胞内信号传导，白细胞运输，细胞应答损伤，和其它过程（3）中发挥作用。尽管存在这些突出的作用，研究表明，基因缺失或抑制个别亲环不严重影响正常的生理。因此，亲环似乎有助于，但不为生理稳定性绝对必要的在正常条件下。

与此相反，亲环已示出由加剧的病理过程和传播疾病表型（4），以发挥在许多疾病和损伤的条件关键作用。例如，亲环素D活性促进线粒体转换孔开放和线粒体介导的细胞死亡缺血再灌注等疾病涉及氧化应激和细胞内钙超载。在许多炎性疾病，分泌亲环引起嗜中性粒细胞，淋巴细胞和巨噬细胞的过度积累和活化。亲环表达上调在几种类型的癌症，其可以协助转移。在各种类型的肝病亲环参与炎症，纤维化和细胞死亡（5）。相反，亲环抑制是横跨实验疾病模型，包括用于心脏发作，中风，脑外伤，多发性硬化，ALS，阿尔茨海默氏，动脉粥样硬化，哮喘和关节炎的频谱保护。因此，亲环是许多疾病的有吸引力的治疗靶标。


在传染病亲环
 
亲环也起着重要作用的许多病毒，细菌和其它病原体（6）的生命周期。被挟持并利用宿主细胞亲环复制和传播疾病的病毒包括丙型肝炎病毒（HCV），人类免疫缺陷病毒（HIV-1），B型肝炎病毒（HBV），和多个冠状（例如SARS）。 HCV和HIV-1是这是最好的形容环素的作用（7）的病毒。在HCV感染，亲环素A，势必由非结构蛋白，NS5A，这是必要的病毒复制。正确的NS5A功能是依赖于亲环素A异构酶活性。在HIV-1感染，亲环素A结合这似乎稳定衣壳核心，促进核条目，并最终有利于反转录病毒衣壳。亲环由HIV-1结合也用来逃避免疫识别在受感染的巨噬细胞的机制。因此，亲环蛋白抑制剂站是下一代的广泛作用抗病毒药物的一些我们这个时代最流行的病毒性疾病。


Ciclofilin制药“CPI化合物

Ciclofilin制药公司的环孢菌素化学，亲环蛋白抑制剂的骨干，全面的筛查方案的专业知识，导致很多专利化合物的发现具有较高的体外效力（低纳摩尔）环素的抑制，低毒性，优良的药代动力学和药效学特性。此外，在我们的化学平台的灵活性意味着化合物是可定制的，以满足特定的疾病的需要。

CPI-431-32是Ciclofilin制药公司的领先医药候选人难以治疗肝炎患者。 CPI-431-32源于几年的非临床测试，优化，以及第三方验证。所述化合物有效抑制HCV和体外HIV-1，包括在一个共同感染模型同时抑制这些病毒。与许多抗病毒剂直接针对病毒（直接作用的抗病毒剂;的DAA），CPI-431-32靶向宿主亲环，因此具有较高的屏障药物耐药性的出现。 CPI-431-32还演示了正在对所有HCV基因型高度有效的，包括基因3型的优势（即pangenotypic），不像大多数HCV的DAA这表明对HCV基因型3 Ciclofilin制药公司的广泛发现和优化的方案要少得多的抗病毒效力已经奠定了它的先导化合物，通过临床前毒理学试验的调查新药申请，并提交快速发展。