Inhibitors of polymerase/processivity factor interaction as anti-CMV agents

作为抗 CMV 药物的聚合酶/持续合成因子相互作用的抑制剂

• 批准号: 7686146
• 负责人: Steven M Firestine
• 金额: $ 18.21万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686146
• 关键词: Adopted; Binding; Biochemical; Biological Assay; Biological Availability; Biological Process; Chemicals; Child; Clinical; Complex; Computer Simulation; Critical Illness; Cytomegalovirus; Cytomegalovirus Infections; DNA biosynthesis; Databases; Development; Disease; Foundations; Funding; Future; Goals; Grant; Herpesviridae; Immunocompromised Host; Investigation; Laboratories; Lead; Learning; Libraries; Life; Modeling; Molecular; Molecular Conformation; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polymerase; Positioning Attribute; Proteins; Protocols documentation; Reporting; Research; Screening procedure; Structure-Activity Relationship; Testing; Therapeutic Agents; Time; Toxic effect; United States; Viral; Virus; Work; base; congenital infection; design; drug development; expectation; hearing impairment; inhibitor/antagonist; innovation; interest; novel; novel therapeutics; pharmacophore; protein protein interaction; public health relevance; scaffold; viral DNA

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) infection is the most common congenital infection in the United States and is a leading cause for hearing loss in children. CMV infection is also a major problem for immunocompromised patients, where CMV infections frequently result in life threatening complications. Unfortunately, existing drugs have poor bioavailability and toxicity profiles which limit their use to only the most critically ill patients. Thus, there is a critical need to develop potent, safe and efficacious drugs for the treatment of CMV. Our laboratory has a long standing interest in the development of medicinal agents directed towards the inhibition key protein-protein interactions involved in critical biological processes. The objective of this application is to develop agents that target a critical, virally-specific protein-protein interaction involved in viral DNA synthesis. Our targeted interaction occurs between the virally encoded polymerase (UL54) and its processivity factor (UL44). Previous studies have shown that this interaction is required for viral viability. The central hypothesis of this R21 grant is that compounds that attach to the UL54-binding pocket of UL44 will inhibit the formation of the UL44:UL54 complex and thus inhibit viral replication. Our hypothesis has been formulated based upon a variety of studies that show that inhibition of the protein-protein interaction between UL44 and UL54 halts viral replication and our preliminary studies which have used computational and rational design to create compounds that inhibit complex formation. Exploration of compounds that inhibit the UL44:UL54 interaction will be done following according to two specific aims: 1. Identify novel inhibitors of the UL54:UL44 complex based upon mimicking the ?-helix of the C-terminus of the UL54 protein. 2. Identify novel inhibitors of the UL54:UL44 complex by in silico pharmacophore screening of databases of commercially available compounds. At the conclusion of this study, we expect that a foundation for a new class of anti-CMV agents will be laid, which in turn, will provide the basis for future intensive medicinal chemistry efforts. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) infection is the most common congenital infection in the United States and major problem for immunocompromised patients. Unfortunately, existing agents to treat CMV are less then ideal. As an outcome of the proposed investigations, we expect to develop new therapeutic agents targeted to the disruption of a critical protein-protein interaction within CMV DNA replication. This contribution is significant because it is expected to provide new anti-CMV agents that will function on a viral target different from existing therapies and once such therapies become available, there is the expectation that these agents will positively impact the treatment of CMV in children and immunocompromised patients. Finally, the information learned during the development of inhibitors of the UL44:UL54 interaction in CMV should be applicable to other herpesviruses which have been demonstrated to require a similar protein-protein interaction.

描述（由申请人提供）：巨细胞病毒（CMV）感染是美国最常见的先天性感染，是儿童听力损失的主要原因。对于免疫功能低下的患者来说，CMV感染也是一个主要问题，在该患者中，CMV感染经常导致威胁生命并发症。不幸的是，现有药物的生物利用度和毒性概况差，仅将其使用限制在最严重的患者中。因此，迫切需要开发有效，安全有效的药物来治疗CMV。我们的实验室对针对关键生物学过程涉及的抑制作用关键蛋白质蛋白质相互作用的药用剂的发展具有长期的兴趣。该应用的目的是开发针对与病毒DNA合成有关的关键，病毒特异性蛋白质蛋白相互作用的剂。我们的目标相互作用发生在病毒编码的聚合酶（UL54）及其加工性因子（UL44）之间。先前的研究表明，这种相互作用是病毒活力所必需的。该R21赠款的中心假设是，附着在UL44的UL54结合口袋的化合物将抑制UL44：UL54复合物的形成，从而抑制病毒复制。我们的假设是根据各种研究提出的，这些研究表明，抑制UL44和UL54之间的蛋白质 - 蛋白质相互作用的病毒复制和我们的初步研究，这些研究使用计算和合理设计来创建抑制复合形成的化合物。根据两个具体目的，将进行抑制UL44：UL54相互作用的化合物的探索：1。基于模仿UL54蛋白的C-末端的ul54：U​​L44复合物的新型抑制剂。 2。通过在硅药物团筛选市售化合物的数据库中确定UL54：UL44复合物的新型抑制剂。在这项研究的结论中，我们希望将建立新的抗CMV代理的基础，而这将为未来的强化药物化学工作提供基础。公共卫生相关性：巨细胞病毒（CMV）感染是美国最常见的先天性感染，也是免疫功能低下患者的主要问题。不幸的是，现有的治疗CMV的代理比理想不太理想。作为拟议研究的结果，我们期望开发针对CMV DNA复制中临界蛋白质蛋白质相互作用的新的治疗剂。这项贡献很重要，因为预计将提供新的抗CMV药物，该抗CMV药物将对与现有疗法不同的病毒靶靶标的作用，并且一旦使用这种疗法，这些药物期望这些药物会对儿童中CMV的治疗产生积极影响，并受到免疫强化患者的治疗。最后，在CMV中UL44：UL54相互作用的抑制剂开发过程中所学的信息应适用于其他疱疹病毒，这些疱疹病毒已被证明需要类似的蛋白质蛋白质相互作用。