Prevention of HIV-1 transmission by small-molecule CD4-mimetic entry inhibitors

通过小分子 CD4 模拟进入抑制剂预防 HIV-1 传播

• 批准号: 9411467
• 负责人: NAVID MADANI
• 金额: $ 63.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411467
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Adverse effects; Anti-Retroviral Agents; Antibodies; Antibody Response; Antiviral Agents; Binding; Binding Sites; CCR5 gene; CD4 Antigens; CXCR4 gene; Cells; Dose; Drug Targeting; Environment; Epidemic; Etiology; Event; Formulation; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Immunologic Deficiency Syndromes; Incidence; Income; Infection; Interruption; Investigation; Laboratories; Lead; Life Cycle Stages; Measures; Mediating; Modality; Modeling; Molecular Conformation; Monkeys; Mucous Membrane; Natural Killer Cells; Process; Prophylactic treatment; Proviruses; Research; Sexual Transmission; Structure; Surface; Testing; Time; Vaccines; Vagina; Vaginal Ring; Vaginal delivery procedure; Viral; Viral Reverse Transcription; Virion; Virus; Virus Diseases; Virus Inactivation; Woman; Work; absorption; aqueous; base; cell killing; design; improved; inhibitor/antagonist; mimetics; neutralizing antibody; nonhuman primate; novel; pandemic disease; pre-exposure prophylaxis; premature; prevent; prophylactic; protective efficacy; receptor; research clinical testing; simian human immunodeficiency virus; small molecule; transmission process; vaccine candidate

PROJECT SUMMARY Altering the course of the global AIDS epidemic will likely require the implementation of means to prevent the transmission of human immunodeficiency virus (HIV-1). With no practical HIV-1 vaccine on the horizon, modalities that would allow women to protect themselves from sexually acquired HIV-1 infection could exert an immediate and significant impact on global HIV-1 incidence. An attractive prophylactic approach involves the interruption of virus entry into the host cell, the earliest event in the HIV-1 life cycle. Small-molecule CD4- mimetic compounds (smCMCs) bind within a conserved pocket on the HIV-1 envelope glycoprotein (Env) spike and block the entry of the virus into the cell. In addition to interfering with the binding of HIV-1 to the CD4 receptor on the target cell, smCMCs also induce conformational changes in Env, irreversibly inactivating its function. The binding of smCMCs also renders Env susceptible to inhibition by antibodies that can be elicited by currently available HIV-1 Env vaccine candidates. Thus, in addition to their direct antiviral effect, smCMCs can potentially synergize with vaccine-elicited antibodies to neutralize incoming HIV-1. In this proposal, we will formulate a newly developed smCMC for sustained vaginal delivery via a pod- intravaginal ring. The design parameters of the pod-intravaginal ring will be modified to optimize the release of the smCMC. We will evaluate the vaginal delivery of the smCMC, as well as systemic absorption and potential side effects, in monkeys. We will then examine the ability of the optimized pod-intravaginal ring delivering a smCMC, alone or in combination with an Env-elicited antibody response, to protect monkeys from multiple low- dose intravaginal challenges with a simian-human immunodeficiency virus (SHIV). Establishing the ability of the pod-intravaginal ring to deliver protective concentrations of the smCMC to the vaginal mucosa of monkeys in a sustained manner will set the stage for clinical testing of this prophylactic approach in women.

项目概要 改变全球艾滋病流行的进程可能需要实施预防措施 人类免疫缺陷病毒（HIV-1）的传播。由于尚未出现实用的 HIV-1 疫苗， 允许妇女保护自己免受性传播 HIV-1 感染的方式可以发挥作用 对全球 HIV-1 发病率产生直接而重大的影响。一种有吸引力的预防方法包括 病毒进入宿主细胞的中断，是 HIV-1 生命周期中最早的事件。小分子CD4- 模拟化合物 (smCMC) 结合在 HIV-1 包膜糖蛋白 (Env) 刺突上的保守口袋内 并阻止病毒进入细胞。除了干扰 HIV-1 与 CD4 的结合外 除了靶细胞上的受体外，smCMC 还会诱导 Env 的构象变化，不可逆地使其失活 功能。 smCMC 的结合还使 Env 容易受到可引发的抗体的抑制 目前可用的 HIV-1 Env 候选疫苗。因此，除了直接的抗病毒作用外，smCMCs 可能与疫苗引发的抗体产生协同作用，以中和传入的 HIV-1。 在本提案中，我们将制定一种新开发的 smCMC，用于通过 pod 进行持续阴道分娩。 阴道内环。荚状阴道环的设计参数将被修改以优化释放 SMCMC。我们将评估 smCMC 的阴道输送以及全身吸收和潜力 对猴子的副作用。然后，我们将检查优化的吊舱阴道环提供的能力 smCMC 单独或与 Env 引发的抗体反应结合使用，可保护猴子免受多种低 使用猿猴人类免疫缺陷病毒（SHIV）进行阴道内攻击。 建立 pod 阴道环将保护浓度的 smCMC 传递至阴道的能力 以持续的方式对猴子的阴道粘膜进行试验将为这种预防性药物的临床测试奠定基础 方法在女性中。