Iron Starvation: A novel strategy for HIV and Chlamydia microbicides

说明(申请人提供)：为了控制艾滋病毒的迅速传播，显然需要研究多种方法。一种已显示出减少在非人类灵长类动物中传播的潜力的策略是应用局部杀微生物剂。此外，由于已经证明其他性传播感染也会增加艾滋病毒的传播，因此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不同阶段的方法的组合不仅从减少耐药性的角度来看是可取的，而且也是为了达到相加或协同作用的效果。在这项提案中，我们计划评估具有肼类结构的小抑制分子限制艾滋病毒和衣原体感染的能力。最近我们已经证明了这类化合物在体外能够有效地抑制衣原体的生长。此外，抑制的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受到宿主铁供应的调节。因此，开发具有有效限制艾滋病毒和衣原体生长的共同作用模式的杀微生物剂有可能成为减少这一流行病的有力武器。我们最初计划使用体外系统测试这些抑制剂，以鉴定我们将进一步表征的化合物，如最佳剂量、细胞毒性、受影响的发育阶段和在生殖器环境中的活性。我们确定的具有活性但细胞毒性有限的化合物将被配方为阴道杀菌剂，在HIV Hu-SCID小鼠和衣原体小鼠生殖器感染模型上进行测试。实现这项提案中的目标有可能在抗击艾滋病毒的斗争中发现一件重要的武器。

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.