BIOORGANIC CHEM OF AIDS: CHEMOKINE MIMIC & ANTIVIRAL AGENT DVMT: P CARINII

艾滋病的生物有机化学：趋化因子模拟物

• 批准号: 6121537
• 负责人: VALERIA BALOGH-NAIR
• 金额: $ 10.93万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6121537
• 关键词: AIDS; Mammalia; biological products; biomaterials; biotechnology; immunology; infection; inflammation; lymphatic system; minority institution research support; nucleic acids; orphan disease /drug; technology /technique; virus

AIDS, the acquired immunodeficiency syndrome caused by the HIV-1, the human immunodeficiency virus, is a life-threatening disease spreading around the globe with alarming speed. By the year two thousand it is estimated 40 million people will be infected with HIV. The immunosuppression resulting from HIV infection causes loss of resistance to opportunistic infections in AIDS patients, P. carinii caused pneumonia being the major cause of deaths. The development of vaccines, ideal to combat an infectious disease have not yet resulted in a vaccine that would be effective not only against the laboratory strains but more importantly against the primary strains of HIV. This problem is further aggravated by the hypermutating nature of HIV. Gene therapy, another promising approach is also yet to bear fruit. In the absence of an effective vaccine and clinically successful gene therapies, other approaches must be sought to prevent further spreading of the HIV infection, to circumvent the effect of the virus in already infected individuals, and to prevent and treat the opportunistic diseases associated with AIDS. We propose a biooranic aproach to combat HIV infection, AIDS and PCP associated with it. This will consist of the development of agents that by interaction with macromolecules vital to HIV's survival will block their action. We propose to design and synthesize compounds that will block the entry of the virus into host cells by preventing the binding of gp120 to CD4, compounds that by interfering with the replication mechanism of HIV inhibit it's maturation. Novel types of highly versatile macrocyclic compounds, developed by us in the first phase of the project, are of vital importance in these blocking events. These will be synthesized by the novel macrocyclization reaction we developed during the ongoing project. The first generation of macrocycles, and new macrocycles designed on the basis of leads obtained in cytotoxicity/cytopathicity tests, as well as their metal complexes and conjugates will be targeted against HIV. The macrocycles will be derivatized with spacer-arms, or they will be introduced during the syntheses. Spacer-arms both hydrophilic and hydrophobic will be employed. Metal chelates of amide, imine and polyaza macrocycles will be used to effect oxidative cleavage of protein or nucleic acids components of HIV. These macrocyclic cleavers will be covalently connected to the carriers, such as antibodies and antisense oligonucleotides, so as to effect cleave in a site and sequence specific manner.

艾滋病，由HIV-1引起的获得的免疫缺陷综合征， 人类免疫缺陷病毒是一种威胁生命的疾病 以惊人的速度在全球范围内传播。 到第二年 据估计，有4000万人将感染艾滋病毒。 HIV感染引起的免疫抑制导致 对艾滋病患者的机会性感染的抵抗力，carinii。 导致肺炎是死亡的主要原因。 发展的发展 疫苗，抗击传染病的理想疫苗尚未导致 在一种疫苗中，不仅可以针对实验室有效 菌株，但更重要的是针对艾滋病毒的主要菌株。 这 艾滋病毒的高压性质进一步加剧了问题。 基因疗法，另一种有前途的方法也尚未结出果实。 在没有有效的疫苗和临床成功基因的情况下 疗法，必须寻求其他方法以防止进一步 艾滋病毒感染的传播，以规避病毒的作用 在已经被感染的个人中，并预防和治疗 与艾滋病相关的机会性疾病。 我们提出了一种生物裂缝，以对抗HIV感染，AIDS和PCP 与之相关。 这将包括代理商的发展 通过与艾滋病毒生存至关重要的大分子的相互作用将 阻止他们的行动。 我们建议设计和合成化合物 这将通过防止 GP120与CD4的结合，通过干扰 艾滋病毒的复制机制抑制了它的成熟。 新颖的类型 高度通用的大环化合物，是我们在第一个中开发的 该项目的阶段在这些阻塞中至关重要 事件。 这些将通过新型的大环化合成 我们在正在进行的项目中发展的反应。 第一个 大环和新的大环的产生 在细胞毒性/细胞病理测试中获得的潜在客户以及 他们的金属配合物和缀合物将针对艾滋病毒。 大环将用隔离臂衍生，否则将是 在合成期间引入。 间隔臂都亲水和 将采用疏水性。 酰胺，亚胺和 Polyaza大环将用于实现氧化性裂解 HIV的蛋白质或核酸成分。 这些大环 切割器将共价连接到载体，例如 抗体和反义寡核苷酸，以便在A中裂解 位点和序列特定方式。