Development of Novel Human Herpes Virus Inhibitors

描述（由申请人提供）：人类疱疹病毒（HHV）可导致严重疾病，如癌症和生殖器疱疹。HHV病毒家族表达病毒成熟和衣壳形成所需的蛋白酶，因此具有感染性。这些丝氨酸蛋白酶在其他已知的丝氨酸蛋白酶中是独特的，因为它们仅以二聚体形式具有活性。蛋白质-蛋白质相互作用代表了一种有效的和有吸引力的治疗策略，并且用于设计起作用以防止这种相互作用的药物样分子的方法在过去十年或更长时间内已经增加和改进。在这个项目中，首要目标是充分理解和改进小分子，这些小分子被表征为对许多HHV家族成员具有活性的蛋白质-蛋白质相互作用抑制剂。在目标一中，该项目建议采用X射线晶体学，以充分了解小分子变构抑制剂对两种不同疱疹病毒家族成员（卡波济斯肉瘤相关疱疹病毒（KSHV）和巨细胞病毒（CMV））的结合模式的相似性和差异。x射线晶体学是一种最先进的技术，可以在原子水平上提供宝贵的信息，并可以指导药物设计，并将在aim one中使用。在目标二中，已经被鉴定为潜在的二聚体破坏剂化合物的小分子片段将用核磁共振技术探测，该技术可以鉴定可以连接在一起的不同片段的潜在区域。这些连接的片段可以改善小分子的dug相似性。最后，在目标三中，该项目旨在通过比较新的、改进的化合物与护理标准之一更昔洛韦的疗效来验证该策略的治疗潜力。总的来说，该项目可以提供具有药物性质的化合物，为新的治疗原理提供概念证明，并可能导致治疗导致严重疾病的疱疹病毒感染。

DESCRIPTION (provided by applicant): Human herpesvirus (HHV) causes serious illnesses such as cancer and genital herpes. The HHV family of viruses expresses proteases that are required for viral maturation and capsid formation and, therefore, infectivity. These serine proteases are unique among other known serine proteases in that they are active only in a dimeric form. Protein-protein interactions represent a validated and attractive therapeutic strategy, and methods for designing drug-like molecules that act to prevent such interactions have increased and improved over the past decade or more. In this project, the overarching aims are to fully understand and improve upon small molecules that have been characterized as protein-protein interaction inhibitors active against numerous HHV family members. In aim one, the project proposes to employ X-ray crystallography in order to fully understand the similarities and differences in binding modes of small molecule allosteric inhibitors against two different herpesvirus family members, Kaposis' Sarcoma-associated Herpesvirus (KSHV) and cytomegalovirus (CMV). X-ray crystallography is a state-of-the-art technique that can provide invaluable information at the atomic level and can guide drug design, and will be employed in aim one. In aim two, small molecule fragments that have been identified as potential dimer disruptor compounds will be probed with nuclear magnetic resonance techniques that can identify potential regions of dissimilar fragments that can be linked together. These linked fragments can improve the dug-likeness of the small molecules. Finally, in aim three, the project aims to validate the therapeutic potential of the strategy by comparing the efficacy of novel, improved compounds to that of one of the standards of care, ganciclovir. Overall, this project could provide compounds that are drug-like in nature, provide proof of concept for a novel therapeutic rationale, and could lead to the treatment of herpesvirus infections that cause serious illness.