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

• 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
• 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

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400万人已经死亡。在美国，该病毒已导致60多万人死亡。尽管对减轻病毒传播的非药物干预措施有了很好的了解，并开发了几种高效疫苗，但全球流行病仍在迅速蔓延。在资源有限的情况下，疫苗供应不足，即使在疫苗已广泛供应数月的地方，仍有相当一部分公众拒绝接种疫苗。此外，随着传染性更强的新病毒变体的出现，它们对第一代疫苗所激发的免疫力不那么敏感，已经注意到越来越多的突破性感染。虽然这些突破性感染中的大多数不会导致住院，但有些会导致住院，而且令人严重关切的是，进一步的免疫进化将进一步损害疫苗的效力。尽管在疫苗方面有望取得进一步进展，但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两种抗病毒治疗模式是Remdesivir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外给药，极大地限制了它们的一般效用，特别是在资源有限的情况下。此外，随着病毒刺突蛋白在人群中进化，一些单克隆病毒已经失去了对抗新循环病毒变体的功效。这种进化预计将继续，因为在自然感染期间产生的人体免疫反应形成了关键的病毒表位。在本补充中，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，以开发耐受性良好、对SARS CoV-2和其他冠状病毒的RNA聚合酶具有高水平活性的化合物，这些化合物可以口服给药，并在各种相关组织类型中获得均匀的治疗浓度的活性三磷酸。如果成功，我们预计这些化合物可能在COVID-19和其他冠状病毒感染患者中具有广泛的医疗适用性。

项目成果

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

• DOI: 10.1128/aac.01155-21
• 发表时间: 2021-09-17
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Schooley RT;Carlin AF;Beadle JR;Valiaeva N;Zhang XQ;Clark AE;McMillan RE;Leibel SL;McVicar RN;Xie J;Garretson AF;Smith VI;Murphy J;Hostetler KY
• 通讯作者: Hostetler KY

Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs.

• DOI: 10.1016/j.antiviral.2023.105718
• 发表时间: 2023-11
• 期刊: ANTIVIRAL RESEARCH
• 影响因子: 7.6
• 作者: Mcmillan, Rachel E.;Lo, Michael K.;Zhang, Xing-Quan;Beadle, James R.;Valiaeva, Nadejda;Garretson, Aaron F.;Clark, Alex E.;Freshman, Jon E.;Murphy, Joyce;Montgomery, Joel M.;Spiropoulou, Christina F.;Schooley, Robert T.;Hostetler, Karl Y.;Carlin, Aaron F.
• 通讯作者: Carlin, Aaron F.

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

十个科学原因支持SARS-COV-2的机载传播。

• DOI: 10.1016/s0140-6736(21)00869-2
• 发表时间: 2021-05-01
• 期刊: Lancet (London, England)
• 作者: Greenhalgh T;Jimenez JL;Prather KA;Tufekci Z;Fisman D;Schooley R
• 通讯作者: Schooley R

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: 10.1101/2020.08.26.269159
• 发表时间: 2021
• 期刊: bioRxiv : the preprint server for biology
• 作者: Schooley,RobertT;Carlin,AaronF;Beadle,JamesR;Valiaeva,Nadejda;Zhang,Xing-Quan;Clark,AlexE;McMillan,RachelE;Leibel,SandraL;McVicar,RachaelN;Xie,Jialei;Garretson,AaronF;Smith,VictoriaI;Murphy,Joyce;Hostetler,KarlY
• 通讯作者: Hostetler,KarlY