Aptamer Microbicide Development Program (MDP)

适体杀菌剂开发计划 (MDP)

• 批准号: 7002505
• 负责人: IAN Michael MCGOWAN
• 金额: $ 67.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002505
• 关键词: AIDS education /prevention; HIV infections; antiinfective agents; clinical research; communicable disease control; communicable disease transmission; comorbidity; cooperative study; drug design /synthesis /production; drug screening /evaluation; herpes simplex virus 2; human immunodeficiency virus 1; human papillomavirus; human subject; laboratory mouse; oligonucleotides; patient oriented research; protein binding; virus infection mechanism; virus related neoplasm /cancer; women' s health

DESCRIPTION (provided by applicant): In the absence of a HIV vaccine, and with inconsistent use of condoms, the AIDS pandemic continues to gather momentum. Sexual exposure is the primary route of infection with women becoming disproportionately affected. In this setting, there is an urgent need to develop new female controlled prevention technologies including microbicides. Ideally, microbicides should provide protection against HIV-1 and other common sexually transmitted infections (STIs) such as herpes simplex virus (HSV) and human papilloma virus (HPV). These products should be safe, effective, acceptable and cheap to manufacture. They should also be able to be used in both the vaginal and rectal compartments. The purpose of this grant is to use aptamer technology to generate individual candidate microbicides with activity against HIV-1, HSV-2 and HPV-16. HSV-2 and HPV-16 have been chosen because they are known to increase the risk of HIV-1 transmission (HSV-2) or are linked to the development of cervical and anal cancer (HPV-16). Aptamers are nucleic acid ligands derived from massively complex combinatorial libraries by a process of in vitro evolution, often referred to as systematic evolution of ligands by exponential enrichment (SELEX). Aptamers have the capacity to bind to important protein targets with high affinity and biological consequences including reducing viral infectivity. In this proposal we will test the following hypotheses: (1) Individual antiviral aptamers can be developed that demonstrate efficacy against HIV-1, HSV-2, and HPV-16 using in-vitro cell challenge experiments, (2) Antiviral efficacy can be demonstrated in cervico-vaginal, intestinal, and anal tissue explant systems and is not altered when aptamers are given as single agents or in combination, and (3) Combinations of antiviral aptamers can prevent infection of explant systems when multiple viruses are used in challenge experiments. The study will be undertaken by a consortium based at Oxford University (aptamer discovery), RNA-Tec (aptamer optimization and scale-up) and UCLA (tissue explant studies).

描述（由申请人提供）：在缺乏艾滋病毒疫苗和不一致使用避孕套的情况下，艾滋病的流行势头继续增强。性接触是感染的主要途径，妇女受到的影响尤为严重。在这种情况下，迫切需要开发新的女性控制预防技术，包括杀微生物剂。理想情况下，杀菌剂应该提供保护，防止HIV-1和其他常见的性传播感染，如单纯疱疹病毒（HSV）和人乳头瘤病毒（HPV）。这些产品应该是安全、有效、可接受和廉价的。它们也应该能够同时用于阴道和直肠隔室。这项拨款的目的是利用适体技术产生具有抗HIV-1、HSV-2和HPV-16活性的单个候选杀微生物剂。之所以选择HSV-2和HPV-16，是因为已知它们会增加HIV-1传播（HSV-2）的风险，或者与宫颈癌和肛门癌（HPV-16）的发展有关。核酸适体是通过体外进化过程从大量复杂的组合文库中衍生出来的核酸配体，通常被称为配体的指数富集系统进化（SELEX）。适体具有与重要蛋白靶标结合的能力，具有高亲和力和生物学后果，包括降低病毒传染性。在本提案中，我们将测试以下假设：(1)通过体外细胞攻击实验，可以开发出对HIV-1、HSV-2和HPV-16有效的个体抗病毒适体；(2)在宫颈阴道、肠道和肛门组织外植体系统中可以证明抗病毒效果，并且当适体单独或联合使用时不会改变；(3)当多种病毒在攻击实验中使用时，抗病毒适体的组合可以防止外植体系统感染。这项研究将由牛津大学（适体发现）、RNA-Tec（适体优化和放大）和加州大学洛杉矶分校（组织外植体研究）的一个财团进行。