Mefloquine Hydrochloride

引言疟疾是由疟原虫感染引起的传染性寄生虫病，全球每年有超过2.4亿人感染，造成~60万人死亡。当前，恶性疟原虫几乎对所有类型的抗疟药包括青蒿素及青蒿素类复方药均产生了不同程度的抗性。抗药性疟原虫的出现、演化及蔓延是疟疾防治和根除的主要难题。跨膜转运蛋白MDR1是哺乳类P-gp蛋白的同源物，早期的研究显示MDR1定位于疟原虫的消化泡（digestive vacuole, DV）泡膜。该蛋白可转运不同类型的抗疟药/引起不同的药敏反应而受到耐药性研究领域的广泛关注。然而，调控MDR1亚细胞定位及抗药性发生的机制一直是个谜。2024年2月27日，厦门大学生命科学学院李剑课题组在Nature Communications 发表题为“Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance”的研究论文，该研究揭示疟原虫去泛素化酶UBP1突变体通过调节MDR1的泛素化和改变其细胞定位，介导MDR1对多种抗疟药的外排，引起疟原虫产生多重抗药性。研究人员首先通过甲氟喹（mefloquine）筛选、构建遗传杂交和遗传定位，发现约氏疟原虫的UBP1编码基因与抗药表型相连锁，并新发现两个独特的与抗药性相关的点突变I1560N和P2874T（均为疏水性氨基酸突变为亲水性氨基酸），突变位点分别位于CCR和UCH功能结构域。接着研究人员应用基因编辑技术对敏感性虫株（IP单倍型）和抗性虫株（NT单倍型）的ubp1进行一系列单点和双点等位替换，正向及反向替换的药敏测试结果证明在两个位点同时突变的情形下疟原虫具有多重抗药性，即突变体对甲氟喹、苯芴醇（lumefantrine）及哌喹（piperaquine）等抗疟药（常用作青蒿素类复方的伴侣药物）均产生了抗性。深入的表型分析阐明双点突变不仅损坏UBP1去泛素化酶的生理功能，而且显著降低原虫率和消化泡中疟色素的生成。UBP1蛋白含有3100多个氨基酸，分析显示该蛋白序列存在高度的固有无序域（intrinsically disordered region, IDR），提示其可通过相分离形成无膜细胞器或凝聚体。质谱鉴定和免疫印迹研究表明，MDR1是UBP1酶促作用的底物蛋白。机制分析发现，野生型UBP1形成具功能性的点状凝聚体对MDR1进行去泛素化，脱泛素化的MDR1定位于消化泡膜；而突变型UBP1由于IP→NT突变破坏了凝聚体的形成及酶活性，导致MDR1泛素化水平升高，造成MDR1易位至细胞质膜，此时MDR1可将抗疟药泵出胞外以降低胞内的药物浓度，致使疟原虫获得抗性。最后，研究者使用P-gp抑制剂他立喹达（tariquidar）与甲氟喹等进行联合用药，发现组合用药可显著杀灭抗性疟原虫。模式图（Credit: Nature Communications）该研究发现并解析了一种新的疟原虫抗药机制：UBP1位点突变→凝聚体及酶活性受损→泛素化水平升高致使MDR1从消化泡膜易位至细胞质膜→药物外排→抗药性产生。研究结论对于抗药性的监测，抗疟药研发和联合用药有重要的指导意义。原文链接https://www.nature.com/articles/s41467-024-46006-3责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

--Preclinical studies show that ASC10-A, the active metabolite of double prodrug ASC10, has potent antiviral activities against both monkeypox and SARS-CoV-2 viruses --Ascletis has received the Notice of Issuance from the United States Patent and Trademark Office (USPTO) for the patent application of ASC10 and its derivatives, and their uses to treat multiple virus infections HANGZHOU and SHAOXING, China, Jan. 26, 2023 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") announces that the China National Medical Products Administration (NMPA) has approved the Investigational New Drug (IND) application of ASC10 for monkeypox indication. ASC10 is an oral double prodrug. After oral administration, both ASC10 and single prodrug molnupiravir are rapidly and completely converted in vivo into the same active metabolite ASC10-A, also known as β-D-N4-hydroxycytidine (NHC) or EIDD-1931. Preclinical studies show that ASC10-A has broad spectrum antiviral activities including potent activities against both monkeypox and SARS-CoV-2 viruses. Ascletis has received the Notice of Issuance from the United States Patent and Trademark Office (USPTO) for the patent application of ASC10 and its derivatives, and their uses to treat multiple virus infections including SARS-CoV-2, monkeypox virus and respiratory syncytial virus (RSV). Ascletis is the first Chinese biotech company which has been granted a patent by the USPTO for its in-house developed oral viral polymerase inhibitor and its derivatives. Monkeypox virus is an orthopoxvirus that causes a disease with symptoms similar to smallpox[1]. As of January 25, 2023, over 85,106[2] confirmed cases have been reported globally and monkeypox virus has spread in 110 countries[2] according to data from World Health Organization (WHO). Data from in vitro antiviral cellular assay with infectious monkeypox virus, a study sponsored by Ascletis and conducted at IIT Research Institute (IITRI) of Illinois Institute of Technology in Chicago, U.S., showed that ASC10-A has potent antiviral activity against monkeypox virus, suggesting that ASC10 has the potential to be an effective treatment of monkeypox virus infection. In August 2022, researchers from National Institute of Infectious Diseases, Tokyo, Japan，tested 132 drugs and the results showed that molnupiravir (active metabolite ASC10-A) and other two drugs have potent cellular antiviral activity in the infectious monkeypox virus assay[3]. The rest of 129 drugs such as remdesivir, favipiravir, sofosbuvir and ribavirin, etc. do not have antiviral activities against monkeypox virus[3]. "I'm very glad that the IND application of ASC10 for monkeypox bas been approved by China NMPA, which further validates Ascletis' in-house R&D capabilities on viral diseases. Currently, there is no approved treatment for monkeypox in the world. We hope that ASC10 will make a contribution to the control of monkeypox globally." said Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis. [1] [2] [3] Daisuke Akazawa, Hirofumi Ohashi, Takayuki Hishiki, et al. Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments. bioRxiv preprint. About Ascletis Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to manufacturing and commercialization. Led by a management team with deep expertise and a proven track record, Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has three marketed products, i.e. ritonavir tablets, GANOVO® and ASCLEVIR®, and 22 drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (HBV functional cure), ASC10 and ASC11(oral small molecules for COVID-19 treatment), ASC40 (recurrent glioblastoma), ASC42 (PBC, primary biliary cholangitis), and ASC40 (acne). For more information, please visit . SOURCE Ascletis Pharma Inc.