Dimandelic Acid Ethers As Topical Microbicides For HIV

描述（由申请人提供）：有16，000个新的艾滋病毒病例 每天有超过3610万人感染艾滋病毒/艾滋病。 在世界范围内，绝大多数艾滋病毒新感染是通过以下途径获得的： 性传播是1640万人的主要传播途径 被感染的女人开发用于局部使用以预防HIV的化合物 传播（杀微生物剂）提供了一个有前途的，也许更容易实现 开发有效疫苗的替代方案。但最近的 令人失望的经验，广泛使用的避孕药，壬苯醇醚-9， 强调需要对化合物进行广泛的临床前评价， 抗病毒功效和毒性之前，他们广泛使用的局部 杀菌剂该计划项目赠款将集中在发展一个 基于母体化合物钠的一类新的候选化合物 二扁桃酸醚（SAMMA）。SAMMA具有抗病毒活性， 实验室适应的HIV和单纯疱疹病毒的原始分离株 (HSV)这种性传播疾病是艾滋病毒的主要辅助因子， 没有明显的细胞毒性。它抑制精子功能， 兔子的受精 通过合理的设计合成了一个核的化合物衍生物 实验室，关键结构/功能关系将被确定为 这类化合物的研究旨在定义完整的艾滋病毒（项目1 和3）和HSV（项目2和3）抑制谱，细胞毒性（项目 抑制机制（项目1和2）和避孕 潜力（项目4）。机制研究将扩大初步观察 母体化合物在病毒进入的早期阶段起作用， 通过仔细研究病毒和病毒糖蛋白与 参与附着和进入的细胞膜配体（项目1和2）。 将通过使用原代上皮细胞来检查初始细胞相互作用， T细胞，巨噬细胞和树突细胞。为了更接近地模拟 生殖器粘膜的解剖、生理和免疫环境， 项目3将检查宫颈灌洗和精液的有效性， 以及在人粘膜外植体培养物和小鼠模型中的功效。 HSV。最后，通过在原代细胞和细胞中共培养HIV和HSV， 宫颈粘膜外植体培养，靶向两种病毒的额外益处 将定义局部杀微生物剂。拟议的全面 对这类化合物的评价将决定它是否应该进展到 临床评价

DESCRIPTION (provided by applicant): There are 16,000 new cases of HIV infection everyday with over 36.1 million people living with HIV/AIDS today. Worldwide, the vast majority of new infections with HIV are acquired through sexual transmission, the major route of transmission to the 16.4 million infected women. Compounds that are developed for topical use to prevent HIV transmission (microbicides) offer a promising and perhaps more easily realized alternative to development of an effective vaccine. However, recent disappointing experience with a widely used contraceptive, nonoxynol-9, emphasizes the need for extensive preclinical evaluation of compounds for antiviral efficacy and toxicity prior to their widespread use as a topical microbicide. This Program Project Grant will focus on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has antiviral activity against laboratory-adapted and primary isolates of HIVas well as herpes simplex virus (HSV), the sexually transmitted disease that is a major cofactor for HIV, without apparent cytotoxicity. It inhibits sperm function and prevents fertilization in the rabbit. Through the rational design of compound derivatives synthesized by a core laboratory, critical structure/function relationships will be determined for this class of compounds in studies designed to define the full HIV (Projects 1 and 3) and HSV (Projects 2 and 3) inhibitory spectrum, cytotoxicity (Projects 1,2,3 and 4), mechanism(s) of inhibition (Projects 1 and 2) and contraceptive potential (Project 4). Mechanism studies will extend preliminary observations that the parent compound works at an early step in viral entry for both HIV and HSV by carefully studying viral and viral glycoprotein interactions with cell membrane ligands involved in attachment and entry (Projects 1 and 2). Initial cell interactions will be examined by using primary epithelial cells, T -cells, macrophages and dendritic cells. To more closely simulate the anatomical, physiologic and immunological environment of the genital mucosa, Project 3 will examine the efficacy in cervical lavage and seminal fluid as well as efficacy in human mucosal explant cultures and in a murine model of HSV. Lastly, through co-culture of HIV and HSV in primary cells and in the cervical mucosal explant culture, the added benefit of targeting both viruses with topical microbicides will be defined. The proposed comprehensive evaluation of this class of compounds will determine if it should progress to clinical evaluation.