Anchimerically Activatable Anti-Zika/Dengue ProTides

反嵌合激活的抗寨卡/登革热 ProTides

• 批准号: 10671030
• 负责人: CARSTON R. WAGNER
• 金额: $ 56.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671030
• 关键词: Acute; Address; Anhydrides; Antiviral Agents; Arboviruses; Australia; Autoimmune Diseases; Binding Proteins; Biodistribution; Biological Availability; Blood; Blood Transfusion; COVID-19 treatment; Carboxylic Acids; Cells; Cessation of life; Chemicals; Clinical; Combined Modality Therapy; Culicidae; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Disease Management; Dose; Drug or chemical Tissue Distribution; Epidemic; Ethers; European Union; FDA approved; Fever; Hepatitis C Therapy; Hepatitis C virus; Histidine; Hydrolysis; In Vitro; Intravenous; Ions; Japan; Laboratories; Lead; Liver; Liver Circulation; Maternal-Fetal Transmission; Medical; Metabolism; Microcephaly; Modeling; Nucleosides; Nucleotides; Oral; Periodicity; Permeability; Persons; Pharmaceutical Preparations; Phenols; Phosphorus; Plasma; Probability; Process; Prodrugs; Reporting; Ribonucleosides; Ribose; Rodent; Rodent Diseases; SARS-CoV-2 infection; Series; Sexual Transmission; Sulfhydryl Compounds; Therapeutic; Toxic effect; Vaccines; Viral; Viral Physiology; Viral hepatitis; Virus; Virus Diseases; Water; ZIKA; ZIKV disease; ZIKV infection; Zika Virus; analog; anti-hepatitis C; antiviral drug development; arboviral disease; carboxylesterase; co-infection; design; dosage; esterase; in vivo; interest; intravenous injection; mouse model; novel; novel strategies; nucleoside monophosphate; phosphoramidate; preclinical evaluation; preclinical study; remdesivir; severe COVID-19; success; transmission process

Arboviruses such as, Dengue (DENV) and Zika (ZIKV), have been associated with several global epidemics. DENV infections can result in a mild fever to potentially fatal dengue shock syndrome, dengue hemorrhagic fever and death, while ZIKV infections can result in congenital microcephaly and the development of autoimmune diseases. Initial clinical manifestation of DENV and ZIKV disease are similar and co-infections have been reported. Most challenging, DENV and ZIKV are known to co-circulate, increasing the probability of co-infections, and thus the potential for severe disease. Consequently, since there is no effective vaccine or form of treatment for either virus, the development of anti-ZIKV and anti-DENV therapeutics is an urgent unmet medical need. Over the past decade prodrugs of nucleotides, referred to as ProTides, have been found to have potent antiviral activity. The anti-hepatitis C virus (HCV) drug sofosbuvir (FDA approved 2013) is the most notable ProTide success, since its use in combination therapy can clear Hepatis C virus infections. Recently, a similar ProTide, remdesivir, has been approved by the FDA, Japan, the European Union an Australia for the treatment of severe SARs-CoV-2 infections by intravenous injection. Carboxyesterase-anhydride-HINT1 (CAH) ProTides, such as sofosbuvir and remdesivir, utilize a four step activation process based on initial esterase hydrolysis, carboxylic acid nucleophilic attack at the phosphorous and release of phenol, followed by mixed anhydride chemical hydrolysis, and finally phosphoramidate hydrolysis by hHINT1. Unfortunately, although they can be dosed intravenously, due to high first pass metabolism, CAH-Protides are limited in their use as oral drugs to viral hepatitis. Furthermore, due to the high carboxyesterase activity of rodent plasma, it has been difficult to carry out pre-clinical studies with rodents and translationally relevant dosages of CAH-ProTides. To address the inherent issues surrounding current ProTide approaches, our group has designed an alternative ProTide approach, we refer to as anchimerically HINT1 activated proTides (AHA-ProTides). Our laboratory has demonstrated that AHA-proTides can be designed that are stable, orally bioavailable, cell permeable and dependent on HINT phosphoramidate hydrolysis. Recently, we have also demonstrated that AHA proTides can be prepared with enhanced potency against DENV and ZIKV. Consequently, we propose to the design and develop anti-DENV and anti-ZIKV AHA ProTides that can serve as advanced lead compounds for the potential treatment of both DENV and ZIKV disease.

虫媒病毒，如登革热(DENV)和寨卡病毒(ZIKV)，与几种全球流行病有关。 登革热病毒感染可导致轻微发烧到可能致命的登革热休克综合征，登革热出血热 和死亡，而ZIKV感染可导致先天性小头畸形和自身免疫的发展 疾病。DENV和ZIKV病的初始临床表现相似，并已合并感染 据报道。最具挑战性的是，DENV和ZIKV已知是共同循环的，增加了联合感染的可能性， 因此有可能引发严重的疾病。因此，由于没有有效的疫苗或治疗形式 对于任何一种病毒，开发抗ZIKV和抗DENV疗法都是一个迫切的、尚未得到满足的医学需求。 在过去的十年里，被称为ProTide的核苷酸前体药物被发现具有强大的 抗病毒活性。抗丙型肝炎病毒(HCV)药物索索布韦(FDA批准于2013年)是最引人注目的 ProTide成功，因为它在联合治疗中的使用可以清除丙型肝炎病毒感染。最近，一个类似的 ProTide，redesivir，已被FDA，日本，欧盟和澳大利亚批准治疗 静脉注射严重SARS-CoV-2感染。羧酸酯酶-酸酐-HINT1(CAH)蛋白， 例如索索布韦和瑞美西韦，使用基于初始酯酶水解法的四步激活过程， 羧酸对磷的亲核攻击和苯酚的释放，其次是混合酸酐 化学水解，最后hHINT1的磷酰化水解。不幸的是，尽管他们可能 静脉给药，由于高首次通过代谢，CAH-ProTide作为口服药物的使用受到限制 病毒性肝炎。此外，由于啮齿动物血浆中的羧酸酯酶活性很高，因此很难 对啮齿动物和翻译相关剂量的CAH-ProTide进行临床前研究。 为了解决围绕当前ProTide方法的固有问题，我们小组 设计了一种替代的ProTide方法，我们称之为锚定HINT1激活的ProTide (AHA-ProTdes)。我们的实验室已经证明，AHA-ProTdes可以设计成稳定的， 口服生物利用度，细胞渗透性，并依赖于暗示的磷酰胺水解。最近，我们 我还证明了AHA ProTide可以制备出更强的抗DENV效力 和ZIKV。因此，我们建议设计和开发抗DENV和抗ZIKV的AHA 可作为潜在治疗两种DENV的高级先导化合物的ProTide 和寨卡病毒病。

项目成果

Dynamic Long-Range Interactions Influence Substrate Binding and Catalysis by Human Histidine Triad Nucleotide-Binding Proteins (HINTs), Key Regulators of Multiple Cellular Processes and Activators of Antiviral ProTides.

• DOI: 10.1021/acs.biochem.2c00506
• 发表时间: 2022-12-06
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Strom, Alexander;Shah, Rachit;Dolot, Rafal;Rogers, Melanie S.;Tong, Cher-Ling;Wang, David;Xia, Youlin;Lipscomb, John D.;Wagner, Carston R.
• 通讯作者: Wagner, Carston R.