Optimizing Zika NS5 Methyltransferase Inhibitors

优化 Zika NS5 甲基转移酶抑制剂

• 批准号: 10092108
• 负责人: Liqiang Chen
• 金额: $ 23.19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092108
• 关键词: Address; Adult; Amino Acids; Animal Disease Models; Animal Model; Antiviral Agents; Binding Sites; Biochemical; Biological Assay; Biological Availability; C-terminal; Central America; Computer Models; Disease Outbreaks; Drug Kinetics; Enzymes; Excretory function; Flavivirus; Funding Opportunities; Future; Goals; Guillain Barré Syndrome; Human; In Vitro; Innate Immune Response; Isoenzymes; Link; Liver; Metabolism; Methylation; Methyltransferase; Microcephaly; N-terminal; Neurologic; Newborn Infant; Nonstructural Protein; Oral; Permeability; Pharmaceutical Preparations; Plasma; Property; Public Health; RNA Caps; RNA-Directed RNA Polymerase; Research; S-Adenosylhomocysteine; S-Adenosylmethionine; Solubility; South America; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Vaccines; Viral; Virus; Virus Replication; ZIKA; ZIKV infection; Zika Virus; absorption; analog; aqueous; base; combat; design; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; lead optimization; novel; response; scaffold; screening; small molecule; therapeutically effective; viral RNA

ABSTRACT Zika Virus (ZIKV) has emerged as a global public health threat because of its recent outbreaks and its link to microcephaly in newborns and Guillain-Barré syndrome in adults. To date, there is no vaccine or treatment available, highlighting an urgent need to develop effective therapeutics. Inhibition of ZIKV NS5 methyltransferase (MTase) is a promising anti-ZIKV strategy. However, current ZIKV MTase inhibitors generally suffer from low activity, lack of selectivity, or unfavorable drug-like properties, hindering testing of MTase inhibitors in the animal models of ZIKV infection. We have designed and synthesized a structurally novel inhibitor of ZIKV NS5 MTase, which possessed anti-ZIKV activity without significant toxicity. In this application, we will perform lead optimization to improve the potency, selectivity and drug-like properties of our ZIKV MTase inhibitors, aiming to identify MTase inhibitors that can be used in the ZIKV animal disease models. To accomplish the goal, we propose the following specific aims: Specific Aim 1. Design and synthesize ZIKV NS5 MTase inhibitors and evaluate them in biochemical and antiviral assays; Specific Aim 2. Assess selected ZIKV NS5 MTase inhibitors for their physiochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties; and Specific Aim 3. Determine in vivo PK parameters of advanced ZIKV NS5 MTase inhibitors. We expect that the proposed research will significantly contribute to efforts in developing ZIKV MTase inhibitors as anti-ZIKV therapeutics.

摘要 寨卡病毒（ZIKV）已成为全球公共卫生威胁，因为它最近的爆发和它的联系， 新生儿的小头畸形和成人的格林-巴利综合征。到目前为止，还没有疫苗或治疗方法。 这表明迫切需要开发有效的治疗方法。ZIKV NS 5甲基转移酶的抑制 MTase是一种有前途的抗ZIKV策略。然而，目前的ZIKV MTase抑制剂通常具有低的生物学活性。 活性、缺乏选择性或不利的药物样性质，阻碍了MTase抑制剂在动物中的测试 ZIKV感染模型。我们设计并合成了一种结构新颖的ZIKV NS 5 MTase抑制剂， 其具有抗ZIKV活性而没有显著毒性。在这个应用程序中，我们将执行铅 优化，以提高我们的ZIKV MTase抑制剂的效力，选择性和药物样性质，旨在 鉴定可用于ZIKV动物疾病模型的MTase抑制剂。为了实现这一目标，我们 提出以下具体目标：具体目标1.设计和合成ZIKV NS 5 MTase抑制剂， 在生化和抗病毒检测中对其进行评估;具体目标2.评估选定的ZIKV NS 5 MTase抑制剂 其理化和体外吸收、分布、代谢和排泄（ADME）特性;以及 具体目标3。测定晚期ZIKV NS 5 MTase抑制剂的体内PK参数。我们预计 拟议的研究将大大有助于开发ZIKV MTase抑制剂作为抗ZIKV药物的努力。 治疗学