Novel Methylenecyclopropane Analogues as Anti-Human Herpesvirus 6 and 8 Agents

作为抗人类疱疹病毒 6 和 8 剂的新型亚甲基环丙烷类似物

• 批准号: 8648980
• 负责人: Terry L. Bowlin
• 金额: $ 100万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-11 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648980
• 关键词: Acquired Immunodeficiency Syndrome; Acyclovir; Adult; Animal Model; Bone Marrow; Bone Marrow Transplantation; Cells; Chickenpox; Childhood; Cidofovir; Cytomegalovirus; DNA-Directed DNA Polymerase; Development; Dose; Dose-Limiting; Drug Kinetics; Drug resistance; Exanthema Subitum; Exhibits; Family; Foscarnet; Ganciclovir; Genital system; Goals; HHV-6A; HHV-6B; Health; Herpes zoster disease; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Herpesvirus Type 3; Human; Human Herpesvirus 2; Human Herpesvirus 4; Human Herpesvirus 6; Human Herpesvirus 7; Human Herpesvirus 8; Immunocompromised Host; In Vitro; Individual; Infection; Infectious Mononucleosis; Kaposi Sarcoma; Lesion; Life; Maximum Tolerated Dose; Modeling; Mus; Mutation; NOEL; Nasopharynx Carcinoma; New Agents; No-Observed-Adverse-Effect Level; Nucleosides; Oncogenic; Oral; Organ Transplantation; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Polymerase Gene; Population; Property; Protein Binding; Rattus; Resistance; Safety; Simplexvirus; Small Business Innovation Research Grant; Solid; Testing; Therapeutic; Thymidine Kinase; Toxic effect; Toxicogenetics; Toxicology; Transplant Recipients; Variant; Viral; Virus; Virus Diseases; analog; base; clinical epidemiology; drug resistant virus; gammaherpesvirus; in vivo; inhibitor/antagonist; intravenous administration; member; novel; nucleoside analog; older patient; pathogen; patient population; pre-clinical; resistant strain; scale up; standard care; viral resistance

DESCRIPTION (provided by applicant): The human herpesviridae family contains eight members divided into three subfamilies, designated alpha, beta and gamma. The alpha herpes viruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and varicella zoster virus (VZV). The beta herpes viruses include human cytomegalovirus (HCMV), two variants of human herpes virus 6 (HHV-6A, HHV-6B), and human herpes virus 7 (HHV-7). The gamma herpes viruses include Epstein-Barr virus (EBV) and human herpes virus 8 (HHV-8). Herpes virus infections are commonly acquired, and many present major health concerns, especially among immunocompromised patient populations (e.g., transplant recipients, AIDS patients, and the elderly). Because of the narrow spectrum of current therapeutics, emergence of resistant virus strains, and the limiting toxicities of current treatment options, there is a definite need for new agents that are effective and safe for treating herpes virus infections, particularly those caused by drug-resistant virus strains in the immunocompromised patient. We have previously identified the methylenecyclopropane nucleosides (MCPNs) as potent inhibitors of HCMV, HHV- 6 and HHV-8. The original goal of the SBIR Phase I proposal was to identify new MCPN analogs with even greater anti-HHV6/8 potency and efficacy, while maintaining HCMV activity. We have exceeded that SBIR Phase I goal, and have now identified novel MCPN analogs with a very unusual, broad anti-herpes spectrum of activity that includes the alpha-, beta- and gamma-herpes viruses, including ACV resistant strains. To our knowledge, this broad spectrum activity has not been seen with existing anti-herpes virus agents. The primary objective of this SBIR Phase II proposal is to evaluate a limited number of the most potent MCPNs in murine toxicity, PK/PD, and efficacy (HSV/CMV/VZV) in animal models to identify a final broad- spectrum anti-herpes virus preclinical candidate, and backup compound, to advance into IND enabling rat GLP toxicology and safety pharmacology studies.

描述（由申请人提供）：人类疱疹病毒科包含八个成员，分为三个亚科，指定为α、β和γ。甲型疱疹病毒包括单纯疱疹病毒1型(HSV-1)、单纯疱疹病毒2型(HSV-2)和水痘带状疱疹病毒(VZV)。 β疱疹病毒包括人类巨细胞病毒(HCMV)、人类疱疹病毒6型的两种变种(HHV-6A、HHV-6B)和人类疱疹病毒7型(HHV-7)。 γ疱疹病毒包括EB病毒(EBV)和人类疱疹病毒8(HHV-8)。疱疹病毒感染通常是获得性的，许多感染会带来严重的健康问题，特别是在免疫功能低下的患者群体中（例如移植受者、艾滋病患者和老年人）。由于当前治疗方法的窄谱、耐药病毒株的出现以及当前治疗方案的有限毒性，确实需要有效且安全的新药剂来治疗疱疹病毒感染，特别是免疫功能低下患者中由耐药病毒株引起的感染。我们之前已经确定亚甲基环丙烷核苷 (MCPN) 是 HCMV、HHV-6 和 HHV-8 的有效抑制剂。 SBIR I 期提案的最初目标是鉴定具有更高抗 HHV6/8 效力和功效的新 MCPN 类似物，同时保持 HCMV 活性。我们已经超出了 SBIR 第一阶段的目标，现在已经鉴定出新型 MCPN 类似物，具有非常不寻常的、广泛的抗疱疹活性谱，包括 α、β 和 γ 疱疹病毒，包括 ACV 耐药株。据我们所知，现有的抗疱疹病毒药物尚未发现这种广谱活性。该 SBIR II 期提案的主要目标是在动物模型中评估有限数量的最有效的 MCPN 在小鼠毒性、PK/PD 和疗效 (HSV/CMV/VZV) 方面的作用，以确定最终的广谱抗疱疹病毒临床前候选药物和备用化合物，以推进 IND 阶段，从而实现大鼠 GLP 毒理学和安全药理学研究。

项目成果

Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.

• DOI: 10.1016/j.antiviral.2021.105018
• 发表时间: 2021-03
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Hagen NR;Nguyen ML;Williams JD;Bowlin TL;Gentry BG
• 通讯作者: Gentry BG