The goal of this clinical trial is to evaluate the effectiveness of sofosbuvir/daclatasvir combination for children aged ≥ 6 years old and adolescents with active HCV infection in Cambodia

开始日期2023-08-07

申办/合作机构

ANRS, Emerging Infectious Diseases

IRCT20200408046987N2

/ Recruiting临床2/3期IIT

Determination the therapeutic effect of Ivermectin and Sovodak on patients infected with COVID-19: A clinical trial.

开始日期2020-10-16

申办/合作机构-

NCT05138523

/ CompletedN/A

Observational, Open Label Study With Direct Individual Benefit Assessing the Efficacy and Safety of Sofosdac® 400mg/60mg Tablets (400 mg Sofosbuvir and 60 mg of Daclatasvir) Treatment in Patients With Chronic Hepatitis C (HCV)

A multicentric, observational, open-design study conducted to evaluate the efficacy and safety of Sofosdac® 400mg/60mg tablets treatment in 100 patients with chronic hepatitis C (HCV)

开始日期2019-11-21

申办/合作机构

Beker Laboratories

[+1]

100 项与达卡拉韦/索磷布韦相关的临床结果

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100 项与达卡拉韦/索磷布韦相关的转化医学

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100 项与达卡拉韦/索磷布韦相关的专利（医药）

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项与达卡拉韦/索磷布韦相关的文献（医药）

2021-04-01·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy2区 · 化学

Improved spectral resolution for the rapid simultaneous spectrophotometric determination of sofosbuvir and daclatasvir as anti hepatitis C virus drugs in pharmaceutical formulation and biological fluid using continuous wavelet and derivative transform

2区 · 化学

Article

作者: Motiee, Fereshteh ; Keyvan, Kiarash ; Sohrabi, Mahmoud Reza

In this study, the simultaneous spectrophotometric estimation of Sofosbuvir (SOF) and Daclatasvir (DAC) in synthetic mixtures and tablet formulation in the presence of overlapping spectra was performed based on continuous wavelet transform (CWT) and derivative spectrophotometry (DS) methods without any separation process. The Coiflet (Coif2) and Daubechies (Db3) wavelet families with wavelength of 256 nm and 218 nm were obtained as the best families for the simultaneous determination of SOF and DAC, respectively. Also, the first derivative absorption spectra revealed the best results corresponding to the analysis of SOF and DAC at 237 nm and 291 nm, respectively. The ranges of limit of detection (LOD) and limit of quantitation (LOQ) related to the CWT and DS methods were 2.45 × 10^-3 to 0.5054 and 6.91 × 10^-3 to 0.6027, respectively. Mean recovery values of SOF and DAC in synthetic mixtures for CWT approach were 98.55%, 98.09% and in DS method were 98.78% and 95.83%, respectively. Real samples, including Sovodak tablet and urine was used for accurate simultaneous determination of the mentioned components. Analyzing Sovodak tablet was implemented using high-performance liquid chromatography (HPLC) as a reference method that the results were near to the CWT and DS methods. In order to investigate the existence of significant differences between the methods, analysis of variance (ANOVA) test at the 95% confidence level was performed but no significant differences were observed. In addition, the amounts of SOF and DAC in the complex matrix of biological sample were well predicted by the proposed methods.

2016-11-01·Science China Life Sciences

The 2016 Lasker-DeBakey Clinical Medical Research Award: Innovative hepatitis C virus (HCV) replicons leading to drug development for hepatitis C cure

作者: Zhao, Qinjian ; Xia, Ningshao

The 2016 Lasker-DeBakey Clinical Medical Research Award was given to three scientists working on different stages of the translational sciences on bringing a high efficacious therapy against hepatitis C virus (HCV) infection to a reality. An effective treatment of HCV chronic infection was developed, by a team led by Michael Sofia, using a prodrug approach and the drug PSI-7977 or Sofosbuvir was approved in 2013 less than 28 years after the initial discovery of HCV. This breakthrough was enabled by the availability of the subgenomic HCV replication system, developed by Charles Rice and Ralf Bartenschlager in 1999. The clinically proven Sofosbuvir with remarkable safety and efficacy was designed to enter the hepatocytes readily and to be processed upon cell entry to a triphosphate derivative, becoming a fully activated competitive and high affinity inhibitor for the HCV NS5B, an RNA-dependent RNA polymerase. While hepatitis diseases as a whole still pose a major public health issue globally, according to a WHO report (WHO reference number: WHO/HIV/2016.06, Global health sector strategy on viral hepatitis, 20162021) (http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/)) the past few years has witnessed a major breakthrough in the antiviral treatment therapy for hepatitis C. HCV is one of the two viruses, B and C, for causing significant disease burden globally due to the progression to liver cirrhosis or cancers. It culminated recently with Charles Rice and Ralf Bartenschlager, together with Michael Sofia, winning the 2016 Lasker-DeBakey Clinical Medical Research Award. The discoveries of Rice and Bartenschlager led to the development of functional HCV replicons. Sofia harnessed the power of this newly available tool of “live HCV in the lab” for identification and improvement of anti-HCV drugs, leading to the development of a novel molecule using a prodrug approach, now known as Sofosbuvir (PSI-7977). The milestones in HCV virology and in antiviral drug development are illustrated in Figure 1. The 2016 Lasker Award represents the second time of Lasker Award series recognizing achievement in the HCV field with the 2000 Lasker award on the initial discovery of HCV and the development of screening methods that reduced the risk of its transmission.

2016-02-01·Antiviral Research2区 · 医学

Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus

2区 · 医学

Article

作者: Wu, Ming ; Shao, Yan ; Yu, Xi ; Qing, Jie ; Tang, Ruoyi ; Wang, Yaxin ; Nong, Junxiu ; Luo, Rui ; Sun, Yuna ; Yin, Zheng

Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were >2298.9, >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive effects with alpha interferon (IFNα-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supplement to other types of nucleoside analogs.

项与达卡拉韦/索磷布韦相关的新闻（医药）

2024-03-30

·药明康德

他救回“垃圾桶”里的药物分子，开启了治愈丙肝的新时代

▎药明康德内容团队编辑丙型肝炎病毒（HCV）是一种常见的血源性病原体，其主要感染部位是肝脏。尽管与乙肝相比，丙肝的知名度并不高，但其潜在危害却同样不容忽视。HCV可能引发急性或慢性肝炎，并增加感染者发展为肝硬化、肝功能衰竭和肝细胞癌（肝癌）的风险，且迄今为止尚未有针对性的疫苗被成功研发出来。但好消息是，2013年年底，首款无需干扰素就能高效治愈丙肝的直接抗病毒药物NS5B抑制剂索非布韦（sofosbuvir）获FDA批准上市，彻底变革了丙肝的治疗格局。在临床试验中，索非布韦展示出了对丙肝2型和3型患者100%的治愈率，其诞生是科学家在丙肝攻坚史上树立的一座里程碑。在索非布韦诞生的背后，除了有历代科学家们为HCV治疗药物的开发奠定了坚实的前期研究基础，还有一名药物研究科学家在其中发挥了关键的推动作用。他凭借扎实的化学功底、灵活的头脑、勇于挑战的个性和坚定的信念最终导致了这款被《细胞》杂志称为“这一代人在公共卫生领域取得的最重要成就之一”的疗法的诞生。在今天的文章中，药明康德内容团队将结合公开资料，为大家讲述这位开创了治愈丙肝的新时代的关键科学家迈克尔·索菲亚（Michael J. Sofia）博士的故事。▲Michael J. Sofia博士（图片来源：药明康德内容团队制作）挑战攻克一种难防难治的棘手疾病故事要从2005年索菲亚博士决定离开大型医药公司，加入一家只有15人的小型生物技术公司准备“从头再来”开始说起。在加入这家名为Pharmasset的小公司之前，索菲亚博士已在大型医药公司里贡献了自己20年的青春。很多人到了像他这样的年纪，年轻时的抱负和梦想都已在时光中被渐渐掩埋，但他却越来越按不下心中的那股冲动。索菲亚博士从博士后阶段开始就对黄病毒研究十分感兴趣，自1989年科学家首次鉴定出属于黄病毒科的丙肝病毒后，他就开始对这种与进行性肝病和癌症相关的新型人类病毒进行了小规模的研究。起初，他没想过要寻找能够治疗HCV感染的方法，只是单纯想要更好地了解这种病毒。但几年后发生的一件事改变了他的想法。那时，一名丙肝小患者的家人联系到他想向他寻求治疗丙肝的新疗法。多年来，这个家庭为了给女儿治病四处求医，在标准治疗无效的情况下，他们唯一的选择只有无奈地期盼新药的出现。当时，索菲亚博士只能对他们表示遗憾，但他想为丙肝患者做点什么的想法已经种下。当然，基于对丙肝病毒的了解，他知道这不是一件易事。▲HCV感染的自然史（图片来源：参考资料[5]）HCV是一种高度多样化的病毒，具有多种亚型，这使得科学家们不管是想要制造出一种提供广泛保护作用的疫苗还是开发一款能够全面覆盖多种亚型的疗法都十分困难。因此，最初被用于治疗丙肝的“标准方案”里的两种药物——干扰素（一种具有抗病毒、抗肿瘤和免疫调节特性的多效性细胞因子）和利巴韦林（一种广谱抗病毒药物）都不是专门用来治疗丙肝的。这种标准方案需要连续使用6至12个月，总体治愈率却只有40%左右。并且由于干扰素会产生流感样症状、抑郁和骨髓抑制等严重的副作用，许多患者根本无法坚持完整个疗程。但对丙肝患者来说，他们没有更好的选择了。时间来到了20世纪末，随着丙肝病毒体外培养的难题被攻克，转机出现了。科学家们终于有了能用来筛选丙肝药物的工具，这为开发直接抗病毒药物（direct-acting antiviral agents，DAAs）奠定了基础。索菲亚博士知道，他实现理想的机会来了。作为一名新药开发工作者，没有什么比亲手开发出一款能够造福广大无药可用的患者的有效药物更能令人感到欣慰和满足的了。为了让自己的学识和多年积累下的药物开发经验能更好地发挥其价值，也为了实现自己的一腔抱负，他毅然离开了稳定的工作环境，选择加入了一家专注于抗病毒药物开发的小公司，从搭建新的研发团队开始，尝试走一条前途未卜的路。毕竟，以前从没人能成功过。初到公司就面临棘手难题当时，许多生物技术和医药公司正竞相开发DAAs，最重要的目标就是要摆脱对干扰素的依赖。其中，研究进展最快的要数HCV蛋白酶抑制剂类药物，但这类药物并没能达到研究人员的预期。首先，这些抑制剂也需要与干扰素和利巴韦林联合使用。其次，这类药物也会产生许多不良副作用。不仅如此，它们也无法覆盖多种不同的HCV亚型，并且患者也会迅速对其产生耐药性。▲HCV的基因组结构和DAAs的作用靶点（图片来源：参考资料[4]）那时，索菲亚博士选择加入的生物技术公司正在开发的候选丙肝药物PSI-6130采取的是另一种治疗策略。PSI-6130是一种核苷类似物，靶向NS5B RNA聚合酶。这类药物可以作为DNA或RNA合成的替代物，被引入到新合成的DNA或RNA链中，从而干扰核酸的合成过程，阻止病毒的复制。索菲亚博士刚到公司就面临着一个棘手的问题。尽管PSI-6130在细胞实验中的表现非常突出——它耐受性良好，并且能显著抑制HCV RNA的合成，但该候选分子也有一个硬伤，它在口服时很难被吸收，还会产生一大堆没有活性的尿苷代谢物。为了解决这个问题，索菲亚博士带领团队尝试开发了PSI-6130的前药。简单地说，前药就好比是一种药物的“特洛伊木马”，它们通过对目标药物分子进行修饰，隐藏了目标药物的真实面目。这样一来，药物就能够通过一些原本无法通过的障碍（比如无法进入细胞），更容易被身体吸收。当前药进入体内后，外部的伪装会被解除，目标药物就能够显示出真正的功效。索菲亚博士团队开发的这款名为RG7128的前药的早期临床数据确实相当令人鼓舞。RG7128在单独给药或与干扰素+利巴韦林联合给药时都能抑制HCV的复制。尤其是在不使用干扰素的情况下，RG7128联用HCV蛋白酶抑制剂也能发挥作用，这让研究人员看到了开发出一款能够完全摆脱干扰素的丙肝疗法的希望。但这种前药依然存在局限性，丙肝患者需要每天多次服用以克为单位的药物才能看到临床效果，并且这种前药同样会产生大量无活性的尿苷代谢物。在这样的情况下，Pharmasset公司的一些工作人员认为，如果要开发出一款最终能够上市的丙肝疗法，他们可能需要找到一种更好的药物。索菲亚博士深以为然。救回“垃圾桶”里的药物分子，开启治愈丙肝的新时代索菲亚博士知道，自己所需要解决的问题很多，包括在保持药物良好特性（如HCV亚型覆盖广、不易耐药和具有高选择性）的同时，提高其药效并减少给药频率。此外，这种药物最好还能选择性地靶向HCV所在的肝脏。问题是，要如何找到这样一种药物呢？索菲亚博士的团队随后进行了大量药物结构改造的探索，但始终没能找到比最初发现的PSI-6130更好的候选分子。于是，他们决定重新以原本想要放弃开发的PSI-6130为突破口，继续开展研究。幸运的是，在他同事菲尔·弗曼（Phil Furman）及其团队的帮助下，索菲亚博士理出了一些继续开发的方向。通过研究PSI-6130的代谢过程和作用机制，他们发现PSI-6130的一种尿苷三磷酸（uridine triphosphate）代谢产物正好符合他们理想中的HCV聚合酶抑制剂的特性——它的半衰期更长，可能具有更好的效力并有望实现一天一次的给药频率。接下来的问题就在于，如何让这种活性代谢产物能特异性地在肝脏细胞中生成并发挥作用呢？索菲亚博士想到了肝脏的首过代谢。首过代谢是指，所有药物在消化道被吸收后，首先会通过门静脉系统直接输送到肝脏被代谢和清除。基于这个想法，索菲亚博士及其同事设计了一种磷酰胺前药，该药物是PSI-6130的衍生物，在进入肝细胞后会因首过代谢脱去药物中的磷酸基团，然后代谢为其单磷酸衍生物，并进一步代谢为他们找到的那种有效的HCV聚合酶抑制剂。为了从大量前药类似物中筛选出最佳候选药物，索菲亚博士团队还建立了全新的体外和体内筛选系统。经过一系列全面的筛选，他们最终选择了一种名为PSI-7851的分子作为临床候选药物。在1期临床试验中，这种疗法被证明是安全有效的，且每天只需服用一次。不过PSI-7851实际上是两种异构体分子的混合物，其中一种形式比另一种形式更有效。经过进一步的优化研究，索菲亚博士团队开发了一种新的化学合成方法来制造PSI-7851中疗效更佳的那种异构体，该单一分子被命名为PSI-7977，也就是后来的索非布韦。▲索非布韦的分子结构（图片来源：参考资料[4]）2012年初，吉利德科学公司（Gilead Sciences）收购了Pharmasset公司，并继续开发索非布韦。尽管此前索非布韦就在临床试验中展现了不俗的实力，但2013年1月公布的一项临床试验结果才最终奠定了其在丙肝治疗中的重要地位。在这项针对丙肝2型和3型患者的临床试验中，索非布韦联用利巴韦林在没有干扰素的情况下，只需给药12周，患者的治愈率为100%！这意味着，索非布韦是首款无需干扰素就能高效治愈丙肝的直接抗病毒药物，彻底变革了丙肝的治疗，让患者不再受干扰素副作用的困扰。2013年12月6日，美国FDA批准了索非布韦（Sovaldi）方案用于某些HCV类型患者的治疗。在它获批后，慢性HCV感染者开启了无干扰素治愈丙肝的新时代。而继索非布韦之后，国内外更多DAAs药物被研发上市，让全球丙肝患者看到了治愈的希望。后记在医学史上，只有屈指可数的慢性疾病能够被治愈，丙肝正是其中的一种。2016年，索菲亚博士因其在丙肝药物开发中做出的突出贡献与另外两位优秀科学家共同获得了拉斯克临床医学研究奖。▲2016拉斯克临床医学研究奖获得者（图片来源：拉斯克奖官网）对于索菲亚博士来说，获奖固然令人兴奋，但最令他感到开心的是，他实现了自己的理想，同时改变了许多丙肝患者的人生。在得知他即将获得拉斯克奖后，当年那位找他求药的小患者家属向他发来了祝贺，并告诉他，他们女儿的病已经治愈并过上了幸福的生活。对于一个基础科学家来说，没有什么是比这更好的奖励了。根据《内科学年鉴》上发表的一项新的研究，基于现有的筛查和治疗手段，到2036年，曾经在世界传染病中排名前列的丙肝将成为罕见病，世界卫生组织更是把2030年消灭丙肝作为目标。▲现有的丙肝疗法已能在短短2-3个月内，以90%以上的成功率治愈所有主要类型的丙肝！（图片来源：世界卫生组织）如今，与丙肝的斗争似乎已经进入了尾声，但科学家的努力还没有结束。期待有效的乙肝疫苗被开发出来那一天，人类能够正真消灭这种疾病。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Hepatitis C replicon system and drug development. Retrieved March 30, 2024, from https://laskerfoundation.org/winners/hepatitis-c-replicon-system-and-drug-development/[2] Williams CL. Ralf Bartenschlager, Charles Rice, and Michael Sofia are honored with the 2016 Lasker~DeBakey Clinical Medical Research Award. J Clin Invest. 2016 Oct 3;126(10):3639-3644. doi: 10.1172/JCI90179. Epub 2016 Sep 13. PMID: 27620536; PMCID: PMC5096798.[3] Hepatitis C. Retrieved March 30, 2024, from https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c[4] Palese P. Profile of Charles M. Rice, Ralf F. W. Bartenschlager, and Michael J. Sofia, 2016 Lasker-DeBakey Clinical Medical Research Awardees. Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):13934-13937. doi: 10.1073/pnas.1616592113. Epub 2016 Nov 18. PMID: 27864510; PMCID: PMC5150379.[5] Vilarinho S, Lifton RP. Pioneering a Global Cure for Chronic Hepatitis C Virus Infection. Cell. 2016 Sep 22;167(1):12-15. doi: 10.1016/j.cell.2016.08.038. Epub 2016 Sep 13. PMID: 27634325.[6] Sofia MJ. Enter Sofosbuvir: The Path to Curing HCV. Cell. 2016 Sep 22;167(1):25-29. doi: 10.1016/j.cell.2016.08.044. Epub 2016 Sep 13. PMID: 27634323.免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

上市批准疫苗

2022-08-17

·Science Daily

How hepatitis E tricks the immune system

Over three million people are infected with the hepatitis E virus every year. So far, no effective treatment is available. An international team has investigated which factors are important for the virus in the course of its replication cycle and how it manages to maintain the infection. The researchers analysed various mutations of the virus and found changes that may allow the virus to trick the immune system. Over three million people are infected with the hepatitis E virus every year. So far, no effective treatment is available. An international team has investigated which factors are important for the virus in the course of its replication cycle and how it manages to maintain the infection. The researchers analysed various mutations of the virus and found changes that may allow the virus to trick the immune system. The team from the Department for Molecular and Medical Virology at Ruhr-Universität Bochum led by Dr. Toni Luise Meister, Dr. Daniel Todt and Professor Eike Steinmann reports in the journal PNAS of 15 August 2022. Advantages and disadvantages of mutations Antibodies are an important defence mechanism against viral infections in our body. They specifically bind mostly to surface proteins of viruses to render it harmless. But, viruses have developed strategies to evade this neutralisation. During an infection with the hepatitis E virus, random mutations often give rise to virus variants that can coexist within an infected person. The antiviral agent Ribavirin, which many chronically infected patients receive, can even increase the formation of such variants. The research team took a closer look at eight capsid protein variants from samples of chronically infected patients treated with ribavirin in the laboratory. The team wanted to know: Do the genetic changes bring advantages or disadvantaged for the virus? Do they influence the virus' ability to replicate or its infectivity? "While seven of the investigated mutations behaved exactly like the wild type virus, we found differences in one mutant," reports Toni Luise Meister. This mutation affects the capsid protein, which is essential for packaging the viral particles. "The viruses with this mutation are assembled incorrectly, are probably smaller than the wild type virus, and the capsid protein does not accumulate in the cell," describes Daniel Todt. These particles are not infectious, but are correctly recognised and bound by antibodies of the immune system. "This could be an advantage for the virus. These defective particles could potentially catch antibodies, so that there are no longer enough to neutralise correctly assembled, infectious virus particles," speculates Eike Steinmann. Hepatitis E The hepatitis E virus (HEV) is the main cause of acute viral hepatitis. Around 70,000 people die from the disease every year. After the first documented epidemic outbreak in 1955 to 1956, more than 50 years passed before researchers took a closer look at the issue. Acute infections usually heal on their own in individuals with an intact immune system. In patients with reduced or suppressed immune systems, such as organ transplant recipients or HIV-infected patients, HEV can become chronic. HEV is also particularly threatening for pregnant women.

抗体

2022-07-20

·Science Daily

Cellular protein identified as possible drug target to combat Lassa hemorrhagic fever

Experimental approach could uncover new treatment options for the virus, which is highly prevalent in Western Africa. Scripps Research in collaboration with the La Jolla Institute for Immunology have used a novel strategy to identify and study host cell proteins that contribute to multiplication of Lassa virus, a virus that causes a severe hemorrhagic fever disease. The discovery could lead to potential new drug targets for treating the disease. Lassa virus (LASV) is highly prevalent in Western Africa. The virus is typically transmitted to humans via contact with aerosols or the droppings and secretions of infected rodents. Infected individuals can develop Lassa fever (LF), a hemorrhagic fever disease associated with high morbidity and mortality. Notably, many LF survivors experience long-term side effects including sensory-neural hearing loss. Other than off-label use of ribavirin- which is of limited and controversial efficacy- there are no treatments for LF, nor any licensed vaccines. The research, led by Juan Carlos de la Torre, PhD, of Scripps Research, in collaboration with the laboratory of Erica Ollmann Saphire, PhD, at La Jolla Institute for Immunology, was published in the Proceedings of the National Academy of Sciences (PNAS) on July 18, 2022. To identify host cell proteins that contribute to LASV replication, the researchers implemented a new strategy that combined proximity proteomics with the use of a non-infectious cell-based LASV minigenome system that recreates the molecular processes involved in LASV replication. Proximity proteomics fuses a protein of interest to an enzyme that will label nearby proteins with a chemical tag, which facilitates their identification. "Viruses don't operate in isolation," says Saphire. "They hijack and require molecules of the cell for their own purposes." De la Torre compares the process to the way social networks can "leave traces of interactions" and provide information about how people might relate to one another, for example, whether two users are located in the same city or household, or if they are family members or acquaintances. "Just as with social media users, some interactions between proteins make sense, and you can infer relationships between the two," he says. "Other protein interactions are casual or accidental and don't mean anything, but, for many others, further investigation is required to uncover their biological implications." With this combined approach, they were able to identify 42 cellular proteins likely to play a role in the replication and spread of LASV. One of the identified host proteins-GSPT1-might be a potential drug target, as CC-90009, a drug that specifically targets and degrades GSPT1, exhibited antiviral activity against LASV without cytotoxicity. CC-90009 is currently in phase 1 clinical development for the treatment of acute myeloid leukemia, raising the possibility of its repurposing as an antiviral against LASV. De la Torre notes that because this method of identifying viral-host cell protein interactions of interest can be done without the live, infectious LASV, this strategy does not require a biosafety level 4 (BSL4) lab, which are expensive to operate. "We think the experimental approach we used could be a rubric for any other highly pathogenic virus," he says. "You would have to change the components, but conceptually, the same approach could potentially be applied with any highly pathogenic virus requiring BSL4." Furthermore, says de la Torre, the identification of host cell proteins that are required for LASV replication can facilitate the repurposing of drugs currently being used for other indications as antivirals against LASV. "This provides an advantage," he says, "since diseases like Ebola and Lassa are restricted to certain geographical areas, making it unlikely pharmaceutical companies will develop drugs specifically for them. Notably, Lassa and Ebola share a number of host cell proteins, which may facilitate the development of broad-spectrum antivirals by targeting host factors used by these two viruses." He notes that a better treatment for LASV could also have an impact outside of Western Africa, as increased traveling to and from LASV endemic regions has resulted in the importation of LF cases into metropolitan areas outside Western Africa. "People doing humanitarian aid in Western Africa, whether clinical work or social work, can get exposed, return to their home and then develop symptoms," he says. "What happens in many countries outside of Western Africa is that doctors who are not familiar with LF assume the disease is malaria and treat for that. When that doesn't work, by the time they realize what the disease is, it's usually too late." Jingru Fang, Haydar Witwit, George Tsaprailis, and Gogce Crynen of Scripps Research are co-contributing authors of "Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host-directed antivirals." This research was supported by institutional 423 funds of La Jolla Institute of Immunology and NIH/NIAID grants AI125626 and AI128556.

疫苗

100 项与达卡拉韦/索磷布韦相关的药物交易

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10 条最早获批的记录,

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适应症	国家/地区	公司	日期
慢性丙型肝炎	伊朗	RojanPharma Pharmaceutical Company	-

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适应症	最高研发状态	国家/地区	公司	日期
慢性丙型肝炎	临床2期	美国	Bristol Myers Squibb Co.	2014-01-16
慢性丙型肝炎	临床2期	美国	The Johns Hopkins University	2014-01-16
慢性丙型肝炎基因型 3	临床1期	波多黎各	Bristol Myers Squibb Co.	2011-06-01
慢性丙型肝炎基因型 3	临床1期	美国	Bristol Myers Squibb Co.	2011-06-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


P1705 (ERA2020)	N/A	肝细胞癌 Alfa feto protein	165	Ombitasvir/Paritaprevir/Ritonavir (OMV/PTV/RTV) regimen	(襯窪製鹹範蓋醖鬱鏇構) = 廠築齋顧遞選構衊遞觸糧夢餘鑰遞鬱積選壓蓋 (膚廠壓製鏇積遞積選遞 ) 更多	积极	2020-06-06
				Sofosbuvir/Daclatasvir regimen	(襯窪製鹹範蓋醖鬱鏇構) = 衊鬱鹽顧艱衊廠製襯鏇糧夢餘鑰遞鬱積選壓蓋 (膚廠壓製鏇積遞積選遞 )
ASN2019	N/A	慢性丙型肝炎基因型 3 维持	-	Sofosbuvir 400 mg daily/Daclatasvir 60 mg daily	(廠鏇窪遞願願顧糧選襯) = 壓襯範鏇鬱鏇廠鑰構築廠鑰選廠醖築壓製蓋簾 (壓壓衊鏇選製網構鹽齋 )	积极	2019-11-05
				Sofosbuvir 400 mg thrice a week/Daclatasvir 60 mg daily	(廠鏇窪遞願願顧糧選襯) = 廠觸鹽憲選醖願窪鑰鹽廠鑰選廠醖築壓製蓋簾 (壓壓衊鏇選製網構鹽齋 )
EASL2019	N/A	慢性丙型肝炎	40	Ledipasvir/sofosbuvir (LDV/SOF)	鑰膚餘觸鬱築齋簾鬱繭(鹹鏇鹹糧範鏇淵獵鬱鏇) = A significant decrease in ALT was observed 窪鑰膚積膚襯艱選夢壓 (範窪艱獵壓鑰積積廠憲 ) 更多	-	2019-04-11
				Daclatasvir/sofosbuvir (DCV/SOF)
UEGW2017	N/A	慢性丙型肝炎	132	Sofosbuvir/Daclatasvir with ribavirin	顧選醖鹹廠築艱齋鏇淵(鹹構醖鏇齋憲遞鬱築糧) = 蓋積廠鑰積衊餘製範鹽夢繭構遞憲醖鏇憲窪憲 (廠範選壓選製觸鏇遞鹽 )	积极	2017-10-01
NCT02124044 (CTgov)	临床2期	丙型肝炎	30	Asunaprevir+Daclatasvir+BMS-791325 (HIV/HCV GT-1a/1b, 12 Wks ASV/DCV With BMS-791325)	簾鹹鬱鬱鏇艱網醖憲製(範鏇襯顧繭鑰餘壓膚醖) = 窪壓願積鹹憲鬱衊構觸構鏇簾鑰鏇淵積醖糧蓋 (蓋膚顧鹽鬱顧鬱膚襯膚, 觸壓憲鏇膚夢窪網餘簾 ~ 膚窪壓壓鹽廠積積壓齋) 更多	-	2017-04-13
				Asunaprevir+Daclatasvir (HIV/HCV GT-1b, 24 Wks ASV/DCV)	簾鹹鬱鬱鏇艱網醖憲製(範鏇襯顧繭鑰餘壓膚醖) = 遞壓膚鑰壓構獵膚憲艱構鏇簾鑰鏇淵積醖糧蓋 (蓋膚顧鹽鬱顧鬱膚襯膚, 糧鹹衊鹽積鹽壓製醖夢 ~ 窪範齋鹽鏇壓鏇鑰鏇餘) 更多
IAS2015	N/A	合并感染	562	Daclatasvir plus sofosbuvir	(淵鹽淵鹽壓構窪憲醖製) = 夢鹹獵網鏇醖鹽蓋鏇鬱構築簾選鑰遞夢艱觸窪 (積構餘顧膚網遞積壓積 ) 更多	-	2015-01-01
				Daclatasvir plus sofosbuvir plus ribavirin	(淵鹽淵鹽壓構窪憲醖製) = 範膚醖蓋窪範壓觸選鑰構築簾選鑰遞夢艱觸窪 (積構餘顧膚網遞積壓積 ) 更多
NCT01359644 (A1444040, Pubmed) 人工标引	临床2期	慢性丙型肝炎	211	Daclatasvir plus Sofosbuvir (genotype 1 + previously untreated)	(範衊鹽齋遞窪憲憲製顧) = 願壓築鏇繭範餘鬱積淵蓋襯觸鹹範醖觸艱廠製 (願網鏇淵鬱壓蓋憲夢網 )	积极	2014-01-16
				Daclatasvir plus Sofosbuvir (genotype 1 + not have a sustained virologic response with HCV protease inhibitors)	(範衊鹽齋遞窪憲憲製顧) = 構願構鹹艱鏇範選壓範蓋襯觸鹹範醖觸艱廠製 (願網鏇淵鬱壓蓋憲夢網 )