可降解铁载体转运抗结核分子的研究

Tuberculosis (TB), caused by Mycobacterium tuberculosis(Mtb), is one of the most deadly infections on earth. Currently, the main strategy for the treatment of TB is still chemotherapy. Drug resistance Mtb and non-replicating Mtb are the barriers of TB for long term treatment at least six months. Our group has made a thorough discussion about the structure-activity relationships (SARs) of D-ring nitrobenzofuran replacement of natural (+)-calanolide, finding out that they can effectively inhibit both replicating and non-replicating Mtb while tending to be genotoxic to mammalian cells. We propose herein to synthesize conjugates of mycobactin T analogs (Iron carrier secreted by Mtb) and antimycobacterial agents, aiming at specifically delivering antimycobacterial agents into Mtb host macrophages and then releasing the agents under the acidic microenvironment or enzymatic condition(i.e. Cathepsin B protease) of the activated macrophages infected by Mtb, thus effectively inhibiting Mtb. This strategy could avoid the genotoxic activity of small molecules, and may contribute to further increase the antimycobacterial activity, even inhibit the clinical drug resistance and non-replicating Mtb.

全球范围内，结核杆菌Mycobacterium tuberculosis（Mtb）引起的结核病（Tuberculosis, TB）是具有高致死率的传染病之一。目前，治疗TB的主要策略仍然是化学药物治疗，耐药及存在非复制性Mtb是治疗的主要难点。本课题组研究发现天然（+）-calanolide 的D环硝基呋喃衍生物可高活性且选择性地抑制复制性及非复制性Mtb，但具有遗传毒性。本申请书拟合成分枝杆菌分泌的铁载体（mycobactin）类似物及与抗Mtb小分子的可降解共缀物，期望通过新型共缀物将抑菌活性分子靶向递送进入宿主巨噬细胞，在Mtb感染并活化的巨噬细胞内特异地酸敏或者酶敏（Cathepsin B蛋白酶）释放抑菌分子，从而有效抑制潜伏性Mtb。此策略可避免抗Mtb小分子的毒副作用，也很可能会进一步提高小分子的抑菌活性，并对目前临床药物的耐药菌显示抑制作用，尤其对抑制潜伏性结核更加有意义。

由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）感染引起的结核病仍然是全世界主要的细菌感染之一。通过对硝基呋喃香豆素类化合物的抑菌构效关系进行了深入研究，发现其可以有效的抑制复制型和非复制型结核分枝杆菌，但对哺乳动物有基因毒性。为了避免基因毒性，采取与细菌分泌的铁载体（mycobactin T）共缀的策略。在我们的工作中以16步、总收率14%完成了mycobactin T全合成。研究发现NFCs的抑菌机制是通过Rv2466c蛋白发挥作用，Rv2466c是Mtb分泌的一种依赖于MSH的硝基还原酶，NFCs类化合物通过Rv2466c的还原起到杀菌作用。NFCs与Rv2466c和MSH形成三元复合物是通过与W21，N51和Y61结合，并被Rv2466c特异性还原，并发出高水平的荧光。进一步的临床研究表明，新型荧光NFCs探针可作为及时的高通量和低成本检测方法，用于活结核分枝杆菌（Mtb）的快速检测。

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