Iron Starvation: A novel strategy for HIV and Chlamydia microbicides

描述（由申请人提供）：为了控制艾滋病毒的快速传播，显然需要研究多种方法。已显示有可能减少非人类灵长类动物传播的一种策略是局部使用杀微生物剂。此外，由于已经证明其他性传播感染也可以增加艾滋病毒的传播，可以有效减少其他性传播感染传播的杀微生物剂也可能是减少艾滋病毒传播的一种策略。针对艾滋病毒和性传播感染发展周期的不同阶段的方法组合是可取的，不仅从减少耐药性的角度来看，而且从获得加性或协同效应的角度来看。在这个提议中，我们计划评估具有腙结构的小抑制剂分子限制HIV和衣原体感染的能力。最近我们已经证明这类化合物能够有效地在体外限制衣原体的生长。此外，抑制机制似乎与宿主铁储存的可逆耗尽有关。有证据表明，艾滋病毒的发展也可以通过宿主铁供应来调节。因此，开发具有共同作用模式的杀微生物剂，有效地限制艾滋病毒和衣原体的生长，有可能成为减少这种流行病的有力武器。我们最初计划使用体外系统测试这些抑制剂，以确定我们将进一步表征的化合物，最佳剂量，细胞毒性，受影响的发育阶段和生殖环境中的活性。我们发现的具有活性但细胞毒性有限的化合物将被配制成阴道杀微生物剂，在HIV - scid小鼠和衣原体小鼠生殖器感染模型中进行测试。实现这一建议的目标有可能为抗击艾滋病毒的斗争发现一个重要的武器。

DESCRIPTION (provided by applicant): In order to control the rapid spread of HIV it is clear that multiple approaches need to be investigated. One strategy that has shown the potential to reduce transmission in non-human primates is the application of topical microbicides. In addition since it has been demonstrated that other sexually transmitted infections can also increase the transmission of HIV, microbicides that can effectively decrease the spread of other STIs may also be a strategy to decrease HIV transmission. Combinations of approaches that target different stages of the HIV and STIs developmental cycle are desirable not only from the standpoint of reducing resistance but also to attain an additive or synergistic effect. In this proposal we plan on evaluating the ability of small inhibitor molecules with a hydrazone structure to limit the infection of HIV and Chlamydia. Recently we have demonstrated that this class of compounds is able to effectively restrict the growth of Chlamydia in vitro. Furthermore the mechanism of inhibition appears to be linked to the reversible depletion of host iron stores. There is evidence that HIV development can also be modulated by host iron supplies. Therefore, development of microbicides with a common mode of action effective at limiting the growth of both HIV and Chlamydia has the potential to be a powerful weapon in the reduction of this epidemic. We initially plan to test these inhibitors using in vitro system to identify those compounds we will characterize further as to, optimum dose, cytotoxicity, stage of development affected and activity in a genital environment. Compounds that we identify that are active yet have limited cytotoxicity will be formulated as a vaginal microbicide to be tested both in a HIV hu-SCID mouse and Chlamydia mouse genital infection model. Achievement of the aims in this proposal has the potential to uncover an important weapon in the battle against HIV.