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

项目总结 要改变全球艾滋病流行的进程，可能需要采取措施防止 人类免疫缺陷病毒(HIV-1)的传播。由于没有实用的HIV-1疫苗即将问世， 使妇女能够防止性获得性感染HIV-1的方式可能会对 对全球艾滋病毒-1发病率的直接和重大影响。一种有吸引力的预防方法涉及到 中断病毒进入宿主细胞，这是艾滋病毒-1生命周期中最早的事件。小分子CD4- 模拟化合物(SmCMCs)结合在HIV-1包膜糖蛋白(Env)尖峰上的保守口袋内 并阻止病毒进入细胞。除了干扰HIV-1与CD4的结合外 靶细胞上的受体，smCMCs也会诱导Env的构象变化，不可逆转地不激活其 功能。SmCMCs的结合也使Env容易受到可引发的抗体的抑制 由目前可用的HIV-1 Env候选疫苗。因此，除了它们的直接抗病毒作用外，SMCMCs 可以潜在地与疫苗引发的抗体协同作用，中和传入的艾滋病毒-1。 在这项建议中，我们将制定一种新开发的经吊舱持续阴道分娩的SMCMC- 阴道内环。将修改吊舱-阴道内环的设计参数，以优化释放 SMCMC。我们将评估smCMC的阴道释放，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-阴道内环的能力 SmCMC，单独或与环境诱导的抗体反应结合使用，以保护猴子免受多种低度... 阴道内注射猴-人类免疫缺陷病毒(SIV)。 建立吊舱-阴道内环将保护性浓度的smCMC输送到 持续的猴阴道黏膜将为该避孕药的临床试验奠定基础 在女性中采取的方法。

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.