Development of Sustained-Release Anti-coronavirus Nucleoside Phosphonate compounds

缓释抗冠状病毒核苷磷酸酯化合物的开发

基本信息

批准号：
10396190
负责人：
Robert Turner Schooley
金额：
$ 16.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-21 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396190
关键词：
2019-nCoV Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Bioavailable Bypass COVID-19 COVID-19 patient Cell Line Cessation of life China Coronavirus Coronavirus Infections DNA-Directed RNA Polymerase Data Development Dose Drug Kinetics Effectiveness Epidemic Epitopes Esters Event Evolution Generations Hepatotoxicity Hospitalization Human Immune response Immunity Immunologics In Vitro Individual Infection Intervention Liver Medical Metabolism Modality Modeling Monoclonal Antibodies Nucleosides Oral Oral Administration Pharmaceutical Chemistry Population Prodrugs Proteins Reporting Resources Rodent SARS-CoV-2 variant Series Site Structure Sustainable Development Synthesis Chemistry Testing Therapeutic Tissues Toxic effect United States Food and Drug Administration Vaccination Vaccines Variant Viral Virus Virus Replication base cell type cytotoxicity design falls improved indexing lead candidate novel nucleoside analog nucleoside diphosphate nucleoside triphosphate parenteral administration phosphonate remdesivir tripolyphosphate vaccine access vaccine efficacy viral transmission

项目摘要

Since the emergence of SARS CoV-2 in China in the fall of 2019, nearly 200 million cases of COVID-19 have been reported globally; over 4 million of these individuals have died. In the US, the virus has been responsible for over 600,000 deaths. Despite a good understanding of non-pharmaceutical interventions that mitigate viral transmission and the development of several highly efficacious vaccines, the global epidemic has continued at a brisk pace. Vaccine availability has been scant in resource limited settings and, even where it has been widely available for months, substantial segments of the public have declined vaccination. In addition, as new more transmissible viral variants emerge that are less susceptible to immunity stimulated by first generation vaccines, an increasing number of breakthrough infections have been noted. Although most of these breakthrough infections do not result in hospitalization, some do, and there is a significant concern that further immunological evolution will further compromise vaccine efficacy. Although further progress on the vaccine front is to be expected, highly effective and well tolerated antiviral agents are sorely needed. At present, the only two modes of antiviral therapy currently approved by the US Food and Drug Administration are Remdesivir and monoclonal antibodies directed at the viral spike protein. Both of these therapeutic modalities require parenteral administration, greatly limiting their general utility, especially in resource limited settings. In addition, as the viral spike protein has evolved within the human population, several of the monoclonals have lost their efficacy against new circulating viral variants. This evolution is expected to continue as critical viral epitopes are shaped by human immune responses generated during natural infection. In this supplement, we propose to apply our synthetic chemistry to the remdesivir base and other nucleosides to develop well-tolerated compounds with high levels of activity against the RNA polymerase of SARS CoV-2 and other coronaviruses that can be delivered orally and achieve uniformly therapeutic concentrations of the active triphosphate in a wide variety of relevant tissue types. If successful, we anticipate that these compounds could have broad medical applicability in patients with COVID-19 and other coronavirus infections.

自 2019 年秋季 SARS CoV-2 在中国出现以来，全球已报告近 2 亿例 COVID-19 病例；其中超过 400 万人已死亡。在美国，该病毒已导致超过 60 万人死亡。尽管人们对减轻病毒传播的非药物干预措施有了很好的了解，并且开发了几种高效疫苗，但全球流行病仍在快速蔓延。在资源有限的环境中，疫苗的供应一直很少，即使疫苗已经广泛使用数月，仍有相当一部分公众拒绝接种疫苗。此外，随着新的更具传染性的病毒变种的出现，它们对第一代疫苗刺激的免疫力不太敏感，人们注意到越来越多的突破性感染。尽管大多数突破性感染不会导致住院治疗，但有些会导致住院治疗，而且人们非常担心进一步的免疫进化将进一步损害疫苗的功效。尽管疫苗方面有望取得进一步进展，但仍迫切需要高效且耐受性良好的抗病毒药物。目前，美国食品和药物管理局批准的抗病毒治疗仅有两种模式：瑞德西韦和针对病毒刺突蛋白的单克隆抗体。这两种治疗方式都需要肠胃外给药，极大地限制了它们的通用性，特别是在资源有限的环境中。此外，随着病毒刺突蛋白在人群中进化，一些单克隆抗体已经失去了对抗新的循环病毒变种的功效。这种进化预计将继续下去，因为关键的病毒表位是由自然感染过程中产生的人类免疫反应形成的。在本补充品中，我们建议将我们的合成化学应用于瑞德西韦碱基和其他核苷，以开发对 SARS CoV-2 和其他冠状病毒的 RNA 聚合酶具有高活性的耐受性良好的化合物，这些化合物可以口服并实现统一的治疗效果各种相关组织类型中活性三磷酸的浓度。如果成功，我们预计这些化合物可能对 COVID-19 和其他冠状病毒感染患者具有广泛的医学适用性。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rethinking Remdesivir: Synthesis, Antiviral Activity, and Pharmacokinetics of Oral Lipid Prodrugs.

重新思考瑞德西韦：口服脂质前药的合成、抗病毒活性和药代动力学。

DOI：
发表时间：
2021-09-17
期刊：
影响因子：
4.9
作者：
Schooley, Robert T;Carlin, Aaron F;Beadle, James R;Valiaeva, Nadejda;Zhang, Xing;Clark, Alex E;McMillan, Rachel E;Leibel, Sandra L;McVicar, Rachael N;Xie, Jialei;Garretson, Aaron F;Smith, Victoria I;Murphy, Joyce;Hostetler, Karl Y
通讯作者：
Hostetler, Karl Y

Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524).

ODBG-P-RVn 的广谱体外抗病毒活性：瑞德西韦母体核苷 (GS-441524) 的口服脂质修饰单磷酸盐前药。

DOI：
发表时间：
2021-08-10
期刊：
影响因子：
0
作者：
Lo, Michael K;Shrivastava;Chatterjee, Payel;Flint, Mike;Beadle, James R;Valiaeva, Nadejda;Schooley, Robert T;Hostetler, Karl Y;Montgomery, Joel M;Spiropoulou, Christina
通讯作者：
Spiropoulou, Christina

Broad-Spectrum In Vitro Antiviral Activity of ODBG-P-RVn: An Orally-Available, Lipid-Modified Monophosphate Prodrug of Remdesivir Parent Nucleoside (GS-441524).

ODBG-P-RVn 的广谱体外抗病毒活性：瑞德西韦母体核苷 (GS-441524) 的口服脂质修饰单磷酸盐前药。

DOI：
发表时间：
2021-12-22
期刊：
影响因子：
3.7
作者：
Lo, Michael K;Shrivastava;Chatterjee, Payel;Flint, Mike;Beadle, James R;Valiaeva, Nadejda;Murphy, Joyce;Schooley, Robert T;Hostetler, Karl Y;Montgomery, Joel M;Spiropoulou, Christina F
通讯作者：
Spiropoulou, Christina F

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs.

重新思考瑞德西韦：口服脂质前药的合成、抗病毒活性和药代动力学。

DOI：
发表时间：
2021-06-07
期刊：
影响因子：
0
作者：
Schooley, Robert T;Carlin, Aaron F;Beadle, James R;Valiaeva, Nadejda;Zhang, Xing;Clark, Alex E;McMillan, Rachel E;Leibel, Sandra L;McVicar, Rachael N;Xie, Jialei;Garretson, Aaron F;Smith, Victoria I;Murphy, Joyce;Hostetler, Karl Y
通讯作者：
Hostetler, Karl Y

Ten scientific reasons in support of airborne transmission of SARS-CoV-2.

支持 SARS-CoV-2 空气传播的十大科学理由。

DOI：
发表时间：
2021-05-01
期刊：
影响因子：
0
作者：
Greenhalgh, Trisha;Jimenez, Jose L;Prather, Kimberly A;Tufekci, Zeynep;Fisman, David;Schooley, Robert
通讯作者：
Schooley, Robert