DICATIONIC DRUGS--TREATMENT FOR AIDS-RELATED INFECTIONS

专用药物——治疗艾滋病相关感染

• 批准号: 2672168
• 负责人: RICHARD TIDWELL
• 金额: $ 61.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672168
• 关键词: AIDS; antiAIDS agent; antiinfective agents; cooperative study; divalent cations; drug design /synthesis /production; microorganism disease chemotherapy; opportunistic infections

The Acquired Immunodeficiency Syndrome (AIDS) continues to be a major health problem in the United States and around the world. In the United States nearly 80% of patients with HIV will die because of opportunistic infections, with Pneumocystis carinii pneumonia the most frequent infection. Although significant strides have been made in the treatment and prophylaxis of P. carinii pneumonia there is clearly a need for new, better tolerated drugs active against Pneumocystis. Likewise, new therapeutic agents are needed for several other important AIDS related pathogens including: Cryptococcus neoformans, Cryptosporidium parvum, Mycobacterium avium, Toxoplasma gondii, Mycobacterium tuberculosis, and Candida albicans. Together with P. carinii, these organisms account for the majority of morbidity and mortality in AIDS patients. The dicationic class of molecules, related to pentamidine, have demonstrated activity against each of these opportunistic pathogens. The studies outlined for this renewal application stem from the convincing data generated during the first two years of funding that show a strong correlation between DNA binding, topoisomerase inhibition and antimicrobial activity of dicationic molecules. We will exploit this relationship in the design and synthesis of more potent and less toxic compounds. In addition, we will employ new strategies toward the development of oral active dicationic molecules. The studies will consist of a highly integrated effort carried out at four separate academic institutions [North Carolina at Chapel Hill (UNC-CH), Georgia State University (GSU), Auburn University (AU), University of Duke University (DU)] and one corporate partner, Pharm-Eco (PE). The synthetic tasks will be divided between GSU and UNC. The group at GSU will work primarily with molecules that include furan and pyrimidine ring systems as spacers between the cationic centers, while the UNC-CH group will focus on benzimidazoles, carbazoles and alpha, omega, dioxyalkanes. The choice of these spacing units is based on our previous studies. The molecular genetics studies into the mechanism of action of the compounds against C. neoformans will be carried out at Duke University. The biophysical studies, including the molecular modeling studies, will be carried out at GSU. The biochemical studies will be performed at UNC-CH. Antimicrobial testing will be undertaken at UNC-CH, AU and DU. Support chemistry (batch chemistry and the synthesis of intermediates) and additional financial support for early phase preclinical development will be the responsibility of PE. Such an integrated approach will maximize the chances of achieving our final goal, the development of new agents for the treatment of AIDS- Associated opportunistic infections.

获得性免疫缺陷综合症（艾滋病）仍然是一个主要的 健康问题在美国和世界各地。在联合 美国近80%的艾滋病病毒感染者会因为机会性感染而死亡 感染，最常见的是卡氏肺孢子虫肺炎 感染 尽管在治疗上已经取得了重大进展， 和预防卡氏肺孢子虫肺炎， 对肺孢子虫有较好耐受性的药物。同样，新 需要治疗剂来治疗其他几种重要的艾滋病相关疾病。 病原体包括：新型隐球菌，微小隐孢子虫， 鸟分枝杆菌、刚地弓形虫、结核分枝杆菌和 白念珠菌与卡氏肺孢子虫一起，这些生物体占 艾滋病患者的发病率和死亡率占绝大多数。该dicationic 与喷他脒有关的一类分子已显示出活性 对抗这些机会致病菌 为这次更新申请概述的研究源于令人信服的 在前两年的融资中产生的数据显示， DNA结合、拓扑异构酶抑制和 双阳离子分子的抗菌活性。我们会利用这一点 在设计和合成更有效和毒性更小的 化合物.此外，我们将采取新的战略， 口服活性双阳离子分子的开发。这些研究将包括 在四个独立的学术机构进行的高度整合的努力， 机构[北卡罗来纳州，格鲁吉亚州，查佩尔山] University（GSU），奥本大学（Au），杜克大学 (DU)]以及一家公司合作伙伴Pharm-Eco（PE）。合成任务将 在GSU和GSU之间分配。GSU的小组将主要与 包括呋喃和嘧啶环系统作为间隔物的分子 在阳离子中心之间，而UNC-CH组将专注于 苯并咪唑、咔唑和α、ω、二氧基烷烃。的选择 这些间距单位是基于我们以前的研究。分子 遗传学研究化合物对C. 新型人将在杜克大学进行。生物物理 研究，包括分子模型研究，将在 GSU。生化研究将在UNC-CH进行。 将在UNC-CH、Au和DU进行测试。 化学和中间体的合成）和额外的财务 负责支持早期临床前开发 的PE。这种综合办法将最大限度地增加实现 我们的最终目标是开发治疗艾滋病的新药物 相关机会性感染。