DEVELOPMENT OF MULTIFUNCTIONAL CHEMOTHERAPEUTIC AGENTS

这项研究是由B. Vithal Shetty博士发起和实施的，他是FDA的客座研究员，也是该项目的联合首席研究员。开发了一种设计新型抗菌药物的新方法。该计划的总体目的是合理设计和合成具有抗菌，抗病毒和抗真菌活性的化合物。理性设计的具体目标是包膜病毒，如疱疹病毒和艾滋病毒。新化合物具有新颖的结构特征，包括一个已知的疏水抗代谢物（例如，氨基金刚烷类似物）通过一个非常亲水的桥连接二聚体。分子的亲水部分对微生物细胞壁的糖蛋白组分具有高亲和力。这种亲和力将毒性部分传递到细胞表面，提供有效活性的机制。有可能抑制艾滋病毒等病毒的复制，并通过将有毒分子附着在病毒外壳上，形成杀死病毒的机制。使用这种策略，对几种化合物进行了检查，其中某些化合物具有令人印象深刻的抗菌效力。一种有效的双金刚烷胺类似物（B.V. Shetty，美国专利号5,221,693）已通过美国国立卫生研究院技术转让计划获得许可，用于开发广谱抗菌药物，特别是用于治疗牙龈感染。这种抗微生物药物设计的双功能方法现在已经扩展到包括将4-喹诺酮类成分纳入结构中。选择4-喹诺酮类药物是因为它们抑制拓扑异构酶II的作用而对原核DNA复制产生选择性作用。真核生物的DNA复制对喹诺酮类抗菌药的作用不太敏感。虽然这些抗菌药据报道很少或没有抗病毒活性，但这似乎是由于病毒包膜的穿透能力差。通过脂亲性桥的合理连接，已经开发出一种策略来传递4-喹诺酮类药物片段穿过病毒外壳。铅化合物已经过测试，发现具有有效的抗艾滋病毒和抗菌活性。优化这些先导化合物的工作已经产生了几种类似物，这些类似物在两个或多个喹诺酮基团之间含有不同的亲水性桥。- HIV，抗病毒，抗菌，药物设计

This research was initiated and carried out by Dr. B. Vithal Shetty, a guest researcher from the FDA who is co-principal investigator of this project. A novel approach to the design of new antimicrobial agents has been developed. The overall purpose of the program is the rational design and synthesis of compounds that have combined anti-bacterial, anti-viral and anti-fungal activity. Specifically targeted in the rational design are enveloped viruses such as herpes viruses and HIV. The new compounds have novel structural features which include a dimeric attachment of a known hydrophobic antimetabolite (for example, aminoadamantane analogues) through a very hydrophilic bridge. The hydrophilic portion of the molecule has a high affinity for glycoprotein components of the microbial cell wall. This affinity will deliver the toxic moieties to the cell surface, providing a mechanism for efficient activity. The potential exists for inhibition of replication of such viruses as HIV and, through the attachment of the toxic molecule to the viral coat, a mechanism for killing the virus. Using this strategy, several compounds were examined and certain of these possessed impressive antimicrobial potency. One potent bis- adamantamine analogue (B.V. Shetty, U. S. Patent No. 5,221,693) has been licensed through the NIH technology transfer program for development as a broad spectrum antimicrobial drug, especially for the treatment of gingival infections. This bifunctional approach to antimicrobial drug design has now been extended to include incorporation of 4-quinolone moieties into the structures. The choice of 4-quinolones stems from their selective effects on prokaryotic DNA replication caused by inhibition of the action of topoisomerase II. Eukaryotic DNA replication is much less susceptible to the action of quionolone antibacterials. Although these antibacterials are reported to have little or no anitviral activity, it seems likely that this is due to poor penetration of the viral envelope. By rational attachment of lipohilic bridges, a strategy has been developed to deliver the 4- quinolone moiety across the viral coat. Lead compounds have been tested and found to have potent anti-HIV, as well as antibacterial activity. Work to optimize these lead compounds has produced several analogs containing varied hydrophilic bridges between two or more quinolone moieties. - HIV, antiviral, antibacterial, drug design