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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：
10459572
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/10459572
关键词：
Acute Address Anhydrides Antiviral Agents Arbovirus Infections Arboviruses Australia Autoimmune Diseases Binding Proteins Biodistribution 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 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 Triad Acrylic Resin Vaccines Viral Physiology Viral hepatitis Virus Virus Diseases Water ZIKA ZIKV disease ZIKV infection Zika Virus analog anti-hepatitis C antiviral drug development base 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 virus development

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.

虫媒病毒如登革热（DENV）和寨卡（ZIKV）与几种全球流行病有关。登革病毒感染可导致轻微发热，甚至可能致命的登革休克综合征、登革出血热和死亡，而ZIKV感染可导致先天性小头畸形和自身免疫性疾病DENV和ZIKV疾病的初始临床表现相似，并且已经发现了合并感染。报道最具挑战性的是，已知DENV和ZIKV共循环，增加了共感染的可能性，从而可能导致严重的疾病。因此，由于没有有效的疫苗或治疗方法，对于任一病毒，抗ZIKV和抗DENV治疗剂的开发是迫切的未满足的医学需求。在过去的十年中，已经发现核苷酸的前药，称为前肽，具有有效的抗肿瘤活性。抗病毒活性。抗丙型肝炎病毒（HCV）药物索非布韦（FDA于2013年批准）是最值得注意的磷酰胺酯的成功，因为它在联合治疗中的使用可以清除丙型肝炎病毒感染。近日，一个类似磷酰胺酯前药，即瑞德西韦，已被FDA、日本、欧盟和澳大利亚批准用于治疗严重的SARS-CoV-2感染。羧酸酯酶-酸酐-HINT 1（CAH）ProTides，例如索非布韦和瑞德西韦，利用基于初始酯酶水解四步活化方法，羧酸亲核攻击磷并释放苯酚，然后是混合酸酐化学水解，最后通过hHINT 1进行氨基磷酸酯水解。不幸的是，尽管他们可以静脉内给药，由于高首过代谢，CAH-原肽作为口服药物的使用受到限制，病毒性肝炎此外，由于啮齿动物血浆的高羧酸酯酶活性，开展啮齿动物临床前研究和CAH-ProTides的预防相关剂量。为了解决围绕当前磷酰胺酯前药方法的固有问题，我们的小组已经设计了一种替代的磷酰胺酯前药方法，我们称之为手性HINT 1激活的磷酰胺酯前药（AHA-ProTides）。我们的实验室已经证明，AHA-proTides可以被设计成稳定的，口服生物可利用、细胞可渗透且依赖于HINT氨基磷酸酯水解。最近我们还证明了AHA前肽可以制备成具有增强的抗DENV效力还有ZIKV因此，我们建议设计和开发抗DENV和抗ZIKV的AHA。可以作为高级先导化合物用于DENV和DENV的潜在治疗的磷酰胺酯前药 ZIKV病