Gp340 and syndecan inhibition based microbicide for HIV

基于 Gp340 和多聚糖抑制的 HIV 杀菌剂

• 批准号: 7926914
• 负责人: DREW WEISSMAN
• 金额: $ 21.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926914
• 关键词: AIDS prevention; Area; Binding; Binding Sites; Biological Assay; Biosensor; Buffers; Cell Communication; Cell Line; Cell surface; Cells; Cervical; Chemicals; Clinical; Collaborations; Data; Development; Dose; Drug Delivery Systems; Drug Formulations; Education; Enhancers; Enzyme-Linked Immunosorbent Assay; Epidemic; Epithelial Cells; Event; Female; Gel; Genital system; Grant; HIV; HIV Enhancer; HIV Infections; Half-Life; Health Benefit; Human; Immunohistochemistry; In Vitro; Infection; International; Life Cycle Stages; Link; Macaca; Macaca mulatta; Mediating; Modeling; Molecular Weight; Pathogenesis; Peptides; Phase III Clinical Trials; Process; Property; Proteins; Public Health; RNA-Directed DNA Polymerase; Research; Reverse Transcriptase Inhibitors; Role; SIV; SRCR proteins; Scavenger Receptor Cysteine-Rich Domain; Sexual Transmission; Side; Site; Staging; Testing; Tissues; Toxicity Tests; V3 Loop; Vaccines; Vagina; Variant; Viral; Virus; base; cellulose sulfate; cost; design; glycoprotein 340; improved; in vitro testing; in vivo; inhibitor/antagonist; macromolecule; member; microbicide; mimetics; novel; novel therapeutics; peptide structure; preclinical study; programs; receptor; simian human immunodeficiency virus; sulfated polymer; syndecan; transcytosis; transmission process; vaginal transmission

DESCRIPTION (provided by applicant): Education and microbicides active against HIV represent the best approaches to controlling the epidemic worldwide in the absence of a protective vaccine. Our research program studies the earliest events in genital tract transmission. We have identified a protein expressed by genital tract epithelial cells that could serve as a potential target for inhibition of transmission of HIV called gp-340. We have demonstrated that gp-340 is expressed on the cell surface of vaginal and cervical epithelial cells, in vivo, in vitro, and ex vivo and binds HIV envelope. Of significance to genital tract transmission, gp-340 binding of virus leads to an increase in both the infectivity and half-life of the virus. Gp-340 expressed by genital tract tissue and cell lines also mediates transcytosis of HIV, the vesicular transport of macromolecules from one side of a cell to the other. A second molecule called syndecan has been studied and shown to have similar trans-infection and transcytosis properties and is also expressed by genital tract cells. We have identified a peptide inhibitor of envelope binding to gp-340 that blocks both gp-340 mediated trans-infection and transcytosis in in vitro and ex vivo models of genital tract transmission. This peptide contains a portion of a motif that inhibits syndecan mediated transinfection, as well, and we will modify this peptide to inhibit envelope binding to both macaque gp340 and syndecan and develop it into a microbicide. This potential role of gp-340 and syndecan to act at a stage of infection after delivery to the lumen of the genital tract but prior to interaction with and infection of target cells is very attractive and novel in microbicide design. We hypothesize that interfering with this process will inhibit or block genital tract transmission. In the initial R21 portion of this proposal, we will establish in vitro macaque systems of genital tract transmission. If we demonstrate that macaque gp340 and syndecan mediate trans- infection and transcytosis and V3 loop derived peptides or improved versions block macaque gp340 and syndecan mediated transinfection and transcytosis, we will proceed with the R33 portion of the grant. The specific aims of this are: microbicide development with in vitro testing and to test the effect of blocking gp340 and syndecan-HIV Env interaction on genital tract SIV transmission in the rhesus macaque vaginal transmission model. Through these specific aims, we will develop a new type of microbicide and determine the role of genital tract gp-340 and syndecan in HIV transmission. If successful, these studies will deliver a new microbicide based on host cell interactions with HIV that promote genital tract transmission to preclinical trial studies.

描述（由申请人提供）：教育和有效对抗艾滋病毒的杀菌剂是在缺乏保护性疫苗的情况下控制全球艾滋病流行的最佳方法。我们的研究项目研究生殖道传播的最早事件。我们已经鉴定出一种由生殖道上皮细胞表达的蛋白质，称为 gp-340，可以作为抑制 HIV 传播的潜在靶标。我们已经证明，gp-340 在体内、体外和离体的阴道和宫颈上皮细胞的细胞表面上表达，并结合 HIV 包膜。对生殖道传播具有重要意义的是，病毒与 gp-340 的结合会导致病毒的感染性和半衰期增加。生殖道组织和细胞系表达的 Gp-340 还介导 HIV 的转胞吞作用，即大分子从细胞一侧到另一侧的囊泡转运。第二种分子称为多配体聚糖（syndecan），已被研究并证明具有类似的转感染和转胞吞作用特性，并且也由生殖道细胞表达。我们已经鉴定出一种与 gp-340 结合的包膜肽抑制剂，可在生殖道传播的体外和离体模型中阻断 gp-340 介导的转感染和转胞吞作用。该肽还含有抑制多配体聚糖介导的转染的基序的一部分，我们将修饰该肽以抑制包膜与猕猴 gp340 和多配体聚糖的结合，并将其开发为杀微生物剂。 gp-340和多配聚糖在递送到生殖道内腔之后但在与靶细胞相互作用和感染之前的感染阶段发挥作用，这一潜在作用在杀微生物剂设计中非常有吸引力和新颖。我们假设干扰这一过程将抑制或阻止生殖道传播。在该提案的最初 R21 部分中，我们将建立体外猕猴生殖道传播系统。如果我们证明猕猴 gp340 和 syndecan 介导转感染和转胞吞作用，并且 V3 环衍生肽或改进版本可以阻断猕猴 gp340 和 syndecan 介导的转感染和转胞吞作用，我们将继续拨款的 R33 部分。其具体目标是：通过体外测试开发杀菌剂，并测试阻断 gp340 和多配体聚糖-HIV Env 相互作用对恒河猴阴道传播模型中生殖道 SIV 传播的影响。通过这些具体目标，我们将开发一种新型杀菌剂，并确定生殖道 gp-340 和 Syndecan 在 HIV 传播中的作用。如果成功，这些研究将基于宿主细胞与艾滋病毒的相互作用提供一种新的杀菌剂，促进生殖道传播到临床前试验研究。