GOSSYPOL DERIVATIVES AS COVALENT CARRIERS OF ANTIVIRALS

这项研究项目的目的是开发新的抗病毒药物 用于治疗由包膜病毒引起的疾病的药物。 这些疾病包括获得性免疫缺陷 综合症。提议的方法的基本原理是利用 棉酚衍生物作为抗病毒药物的内在性质 抗包膜病毒和作为具有亲和力的试剂 包膜。棉酚的衍生品将与 依附于已知的抗病毒药物，以开发一套新的 棉酚部分既是药物载体又是药物载体的药物 和可能发挥协同作用的单独药物 棉酚衍生物的共价加合物和 抗病毒药物。具体目标是： 1)将棉酚衍生物酯化为有前景的抗病毒药物。 抗人类免疫缺陷病毒(HIV)和单纯疱疹 病毒(HSV)，如氮碘胸苷、利巴韦林和阿昔洛韦，以及 测试这些偶联衍生物的体外活性。 2)将棉酚衍生物连接到多肽上，这些多肽 已知对艾滋病毒或流感病毒具有活性，并进行测试 这些共轭衍生物具有体外活性。 本研究的主要方法是合成化学。 需要制备各种棉酚衍生物并附加到 已知抗病毒药物的衍生品。这其中的大部分合成化学 已经开发出来了。这些新药的体外研究 将使用人类T细胞对HIV进行试验；对HSV-II进行试验， 使用Vero细胞；对于流感病毒，使用MDCK细胞。这 方法，它利用逆转录病毒、DNA病毒和RNA 病毒，所有这些都是被包裹的，应该提供一个迹象 这些新的共价连接药物是否普遍有效 抗包膜病毒，或者它们是否表现出特异性 某些被包膜的病毒。

The objective of this research project is to develop new antiviral drugs useful for treatment of disease caused by enveloped viruses. Included among these diseases is Acquired Immunodeficiency Syndrome. The rationale for the proposed approach is to utilize intrinsic properties of gossypol derivatives as antiviral agents against enveloped viruses and as agents with affinities for the envelope membranes. Gossypol derivatives will be convalently attached to known antiviral drugs in order to develop a new set of drugs in which the gossypol moiety is both a vehicle for drug delivery and a separate drug which may exert a synergistic effect after hydrolysis of the covalent adduct of gossypol derivative and antiviral drug. The specific aims are: 1) The esterify gossypol derivatives to promising antivirals against human immunodeficiency virus (HIV) and herpes simplex virus (HSV), such as aziodothymidine, ribavirin and acyclovir, and to test these conjugated derivatives for activity in vitro. 2) To attach gossypol derivatives to polypeptides which are known to be active against HIV or influenza virus, and to test these conjugated derivatives for activity in vitro. The major methodology in this study is the synthetic chemistry necessary to prepare various gossypol derivatives and to attach derivatives to known antivirals. Much of this synthetic chemistry has been developed already. In vitro studies of these new drugs will be carried out with HIV, using human T cells; with HSV-II, using Vero cells; and with influenza virus, using MDCK cells. This approach, which utilizes a retrovirus, a DNA virus, and an RNA virus, all of which are enveloped, should provide an indication whether these new covalently linked drugs are generally active against enveloped viruses or whether they exhibit specificity for certain enveloped viruses.