Development of a Small Molecule Inhibitor for KSHV LANA

KSHV LANA 小分子抑制剂的开发

• 批准号: 8856529
• 负责人: PAUL M LIEBERMAN
• 金额: $ 38.39万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856529
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adsorption; Affect; Affinity; Angiolymphoid hyperplasia; Animal Model; Anti-HIV Agents; B-Lymphocytes; Binding; Biochemical; Biological; Biological Assay; Calorimetry; Cell Survival; Cells; Chemicals; Collaborations; Crystallography; DNA Binding; DNA Binding Domain; DNA biosynthesis; Development; Disease; Drug Design; Drug Kinetics; Episome; Excretory function; Gene Deletion; Gene Expression; Genetic; Goals; HIV; HIV Seropositivity; Health; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; In Vitro; Kaposi Sarcoma; Lead; Libraries; Lymphatic Endothelial Cells; Lymphoid; Lymphoma; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Measures; Metabolism; Methods; Mus; Neoplasms; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pleural effusion disorder; Proteins; Research; Risk; Roentgen Rays; Small Interfering RNA; Structure; Surface Plasmon Resonance; Therapeutic; Titrations; Viral; Viral Genome; Viral Pathogenesis; Viral Proteins; Virus; Xenograft Model; base; biophysical properties; computational chemistry; design; experience; gene repression; high throughput screening; indexing; inhibitor/antagonist; latency-associated nuclear antigen; latency-associated protein; latent infection; next generation; novel; novel therapeutics; prevent; programs; small molecule; treatment strategy; tumor; tumorigenesis

DESCRIPTION: The goal of this research program is to develop and characterize novel small molecule inhibitors of latent Kaposi's Sarcoma Associated Herpesvirus (KSHV) infection. KSHV/Human Herpes Virus 8 (HHV-8) is a human herpesvirus and the causative agent of Kaposi's sarcoma's (KS). KS is a lymphatic-endothelial cell malignancy that occurs most frequently and severely in patients with HIV-AIDS. KS affects about 20% of HIV- positive patients who are not taking anti-HIV drugs. In addition, there appears to be an increase of new cases of KS in patients whose HIV is under control. KSHV has also been implicated in several lymphoid disorders, including pleural effusion lymphoma and Castleman's disease. At present, there are no KSHV-specific therapies that effectively block KSHV infection or latency, and therefore it remains impossible to effectively treat or prevent KSHV-related pathologies. Latent infection and viral pathogenesis require one viral encoded protein, Latency-Associated Nuclear Antigen (LANA), which functions in the replication and maintenance of the viral genome during latency, and alters cellular gene expression programs that promote virus and host cell survival. Genetic and biological disruption of LANA, including siRNA depletion and gene deletion, block viral genome persistence during latent infection. The LANA DNA binding domain (DBD) has been characterized biochemically and structurally, and serves as an ideal target for small molecule inhibition of KSHV infection. The development of a safe and effective inhibitor of LANA would provide an important therapeutic strategy for the treatment of KSHV-associated malignancies. This program builds on the successful completion of a high- throughput screen for small molecule inhibitors of LANA, and on our recent determination of the X-ray crystal structure of the LANA DNA binding domain. The risk of this project is further mitigated by our experience developing small molecule inhibitors targeting Epstein-Barr Virus protein EBNA1 with similar structure and function as LANA. We have used high-throughput screening, crystallography, and structure-based drug design approaches to optimize validated hits into lead compounds that possess mid to low-nanomolar activity for EBNA1. In this R01 proposal, we plan to apply a similar strategy to identify and optimize LANA inhibitors for the treatment of KSHV-related disease.

描述：本研究项目的目标是开发和表征潜伏卡波西肉瘤相关疱疹病毒（KSHV）感染的新型小分子抑制剂。KSHV/人类疱疹病毒8 （HHV-8）是一种人类疱疹病毒，是卡波西肉瘤（KS）的病原体。KS是一种淋巴内皮细胞恶性肿瘤，在HIV-AIDS患者中最常见和最严重。大约20%没有服用抗HIV药物的HIV阳性患者受到KS的影响。此外，在艾滋病病毒得到控制的患者中，KS的新病例似乎有所增加。KSHV还与几种淋巴系统疾病有关，包括胸腔积液淋巴瘤和Castleman病。目前，还没有能够有效阻断KSHV感染或潜伏期的KSHV特异性疗法，因此仍不可能有效治疗或预防KSHV相关病理。潜伏感染和病毒发病需要一种病毒编码蛋白，潜伏相关核抗原（LANA），它在潜伏期间参与病毒基因组的复制和维持，并改变细胞基因表达程序，促进病毒和宿主细胞的存活。LANA的遗传和生物学破坏，包括siRNA缺失和基因缺失，在潜伏感染期间阻断病毒基因组的持久性。LANA DNA结合域（DBD）的生物化学和结构特征，是小分子抑制KSHV感染的理想靶点。开发一种安全有效的LANA抑制剂将为治疗kshv相关恶性肿瘤提供重要的治疗策略。该计划建立在LANA小分子抑制剂的高通量筛选成功完成的基础上，以及我们最近对LANA DNA结合域的x射线晶体结构的测定。我们开发的靶向eb病毒蛋白EBNA1的小分子抑制剂具有与LANA相似的结构和功能，进一步降低了该项目的风险。我们使用了高通量筛选、晶体学和基于结构的药物设计方法来优化验证命中的先导化合物，这些先导化合物对EBNA1具有中低纳摩尔活性。在这个R01提案中，我们计划应用类似的策略来识别和优化LANA抑制剂，用于治疗kshv相关疾病。