Medicinal chemistry core

药物化学核心

• 批准号: 10512621
• 负责人: Adam R Renslo
• 金额: $ 621.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512621
• 关键词: Address; Animals; Antiviral Agents; Antiviral Therapy; Binding; Biochemical; Biological Assay; Biological Sciences; COVID-19; COVID-19 pandemic; Chemistry; Clinical Trials; Collaborations; Communities; Contracts; Country; Data; Development; Disease Outbreaks; Drug Kinetics; Ensure; Event; Family; Family Picornaviridae; Flavivirus; Future; Goals; Hand; Healthcare; Hospitals; Human; In Vitro; Industry Standard; Infrastructure; Knowledge; Lead; Letters; Ligands; Lung; Memory; Metabolic; Metabolism; Modeling; Modification; Mus; Oral; Outcome; Output; Paramyxovirus; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Play; Process; Property; Proteins; RNA Viruses; Risk; Role; Scientist; Series; Severity of illness; Structural Models; Structure; Structure-Activity Relationship; Technical Expertise; Tissue Sample; Togaviridae; Toxicology; Translating; United States; Vaccinee; Vaccines; Variant; Viral; Viral Proteins; Virus; Work; analog; breakthrough infection; chemical synthesis; clinical development; clinical efficacy; clinical translation; design; drug discovery; experience; high risk; improved; in vivo; industry partner; lead optimization; lead series; member; pandemic disease; pharmacokinetics and pharmacodynamics; preclinical development; preclinical evaluation; programs; response; screening; small molecule; small molecule therapeutics; structural biology; unvaccinated; vaccine hesitancy; virology

CORE 3: MEDICINAL CHEMISTRY SUMMARY Despite the development of effective vaccines to address the COVID-19 pandemic, the significant challenges associated with their distribution and administration on a global scale, combined with the issue of vaccine hesitancy, has put a spotlight on the equally urgent need for safe and effective antiviral therapeutics. A readily distributed, orally bioavailable small molecule antiviral agent could play an outsized role in the continuing response to COVID-19 and in future pandemics by reducing the severity of disease for those at highest risk for serious outcomes and thereby curtailing the strain that serious illness puts on hospitals and healthcare infrastructure. The role of the Medicinal Chemistry Core in the larger QCRG Pandemic Response Program is to enable the Project teams to translate their expert knowledge of specific viral families and protein targets into small molecule drug leads that our industry partner Roche could rapidly develop into effective new antiviral therapies. Drug discovery is a highly collaborative enterprise requiring diverse scientific and technical expertise, and this is reflected in the Projects and Cores assembled as part of the QCRG Pandemic Response Program (see Fig. 1). Turning a validated screening ‘hit’ into a drug lead involves an iterative process of compound design and chemical synthesis that is characterized not only by optimization of ligand–target binding, but equally importantly by the optimization of in vivo ‘drug-like’ properties to ensure the molecule will reach its target in an animal and provide a sustained inhibitory effect that produces clinical efficacy. The Medicinal Chemistry Core will leverage the decades of drug discovery experience of its Core Lead Dr. Renslo and Co-Is Dr. Jin and Dr. Shoichet, the expertise of the Projects and Cores, and ADME and PK/Tox assays available at CROs, to convert validated hits into Optimized Leads, guided along this path by our Target Product Profile (TPP) for an antiviral small molecule therapeutics. These Optimized Leads will then be transferred to our industry partner Roche for further pre-clinical and clinical development.

核心3：药物化学 总结 尽管开发了有效的疫苗来应对COVID-19大流行，但重大挑战仍然存在， 与其在全球范围内的分发和管理有关，再加上疫苗问题， 犹豫，把聚光灯放在同样迫切需要安全和有效的抗病毒治疗。易于 分布的、口服生物可利用的小分子抗病毒药物可以在持续的 应对COVID-19和未来的大流行病，降低最高风险人群的疾病严重程度， 严重后果，从而减少严重疾病给医院和医疗保健带来的压力 基础设施演进药物化学核心在更大的QCRG流行病应对计划中的作用 是使项目小组能够将他们对特定病毒家族和蛋白质靶点的专业知识 我们的行业合作伙伴罗氏公司可以迅速开发出有效的新型抗病毒药物 治疗药物发现是一项高度协作的事业，需要各种科学和技术专业知识， 这反映在作为QCRG流行病应对计划一部分的项目和核心中 (see图1）。将经过验证的筛选'命中'转化为药物先导涉及化合物设计的迭代过程 和化学合成，其特征不仅在于配体-靶结合的优化， 重要的是，通过优化体内“药物样”性质，以确保分子将以 动物，并提供产生临床功效的持续抑制作用。药物化学核心 将利用其核心负责人Renminbi博士和共同负责人Jin博士和Dr. Shoichet，项目和核心的专业知识，以及CRO提供的ADME和PK/Tox测定， 我们的目标产品概况（TPP）引导沿着这条路径， 小分子疗法然后，这些优化的潜在客户将被转移到我们的行业合作伙伴罗氏， 进一步的临床前和临床开发。