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.

项目摘要 改变全球艾滋病流行的过程可能需要实施手段以防止 人免疫缺陷病毒（HIV-1）的传播。没有实际的HIV-1疫苗， 允许妇女保护自己免受性获得的HIV-1感染的方式可能发挥 对全球HIV-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 病毒进入宿主细胞的中断，这是HIV-1生命周期中最早的事件。小分子CD4- 模拟化合物（SMCMC）在HIV-1信封糖蛋白（ENV）尖峰上的保守口袋内结合 并阻止病毒进入细胞。除了干扰HIV-1与CD4的结合 靶细胞上的受体，SMCMC还诱导Env中的构象变化，不可逆转地失活 功能。 SMCMC的结合还使可以引起的抗体受到抑制作用。 通过当前可用的HIV-1 Env疫苗候选。因此，除了其直接抗病毒作用外，SMCMCS 可以潜在地与疫苗吸收的抗体协同作用，以中和传入的HIV-1。 在此提案中，我们将制定新开发的SMCMC，以通过Pod-持续进行阴道分娩 弹内环。将修改Pod-Intravaginal环的设计参数，以优化释放 SMCMC。我们将评估SMCMC的阴道递送，以及全身吸收和潜力 副作用，在猴子中。然后，我们将检查优化的Pod-Intravaginal环的能力 SMCMC，单独或与Env引起的抗体反应结合使用，以保护猴子免受多种低低 - 剂量的剂量静脉内挑战，具有猿类 - 人类免疫缺陷病毒（SHIV）。 建立豆荚内环将SMCMC的保护浓度输送到该的能力 猴子的阴道粘膜以持续的方式为这种预防性的临床测试奠定了基础 女性的方法。