Anchimerically Activatable Anti-Zika/Dengue ProTides

反嵌合激活的抗寨卡/登革热 ProTides

基本信息

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
项目类别：
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

项目摘要

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.

诸如登革热（DENV）和Zika（Zikv）之类的arbovirus与几种全球流行病有关。 DENV感染可能导致轻度发烧，以至于潜在的致命登革热综合症，登革热大量发烧和死亡，而ZIKV感染可能导致先天性小头畸形和自身免疫性的发展疾病。 DENV和ZIKV疾病的最初临床表现相似，共同感染一直是报告。众所周知，最具挑战性的DENV和ZIKV是共同循环的，增加了共同感染的可能性，因此，严重疾病的潜力。因此，由于没有有效的疫苗或治疗形式对于任何一种病毒而言，抗ZIKV和抗DENV治疗剂的发展都是紧迫的未满足医疗需求。在过去的十年中抗病毒活性。抗肝炎病毒（HCV）药物Sofosbuvir（FDA批准2013年）是最值得注意的促进成功，因为它在联合疗法中的使用可以清除肝癌病毒感染。最近，类似 remdesivir的fteride已获得日本FDA，欧盟A澳大利亚的批准通过静脉注射的严重SARS-COV-2感染。羧酯酶 - 含盐水Hint1（CAH）蛋白酶，例如sofosbuvir和remdesivir，基于初始酯酶水解利用四步激活过程，羧酸亲核攻击在磷和苯酚的释放中，然后是混合酸酐化学水解，最后通过HHINT1进行磷酰胺水解。不幸的是，尽管它们可以静脉注射，由于初次代谢高，CAH-PROTIDE用作口服药物的限制病毒肝炎。此外，由于啮齿动物等离子体的高羧酸酯酶活性，很难很难通过啮齿动物进行临床前研究，并与CAH-PROTIDE的翻译相关剂量进行。为了解决围绕当前植物方法的固有问题，我们的小组有设计了一种替代的蛋白质方法，我们称为锚式hint1激活的蛋白质（aha-protides）。我们的实验室表明，可以设计AHA-PROTIDE的稳定，口服生物利用，可渗透细胞，并取决于促磷光酰胺水解。最近，我们还证明可以通过增强的DENV效力来制备AHA蛋白酶和zikv。因此，我们建议设计并开发反丹特和抗zikv aha 可以用作高级铅化合物的蛋白质，用于潜在的DENV 和ZIKV病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.