新型脑靶向HIV进入/融合抑制剂的设计及初步评价

In recent years, the entry (fusion) inhibitor targeting HIV envelope protein gp41 has become one of the hot spots in the field of AIDS drug research. Due to the presence of the blood-brain barrier (BBB), traditional HAART drugs can not be effective enter to the brain, leading to the formation of HIV brain reservoir. In order to eliminate the HIV brain reservoir, and then achieve the functional cure of AIDS, the clinical need a class of anti-HIV drugs can penetrate BBB and low side effects...Angiopep-2 is a polypeptide that binds to low-density lipoprotein receptor-associated protein (LRP), which is highly expressed on BBB, and has successfully delivered a variety of drugs into the brain. This study intends to connect Angiopep-2 into T1144, which is the latest generation of HIV polypeptide inhibitor, through different lengths and types of linkers. Thereby allow the entry inhibitor T1144 to obtain brain targeting ability. ..This study will also optimize the linker, evaluate the anti-HIV activity and BBB penetrating ability of candidate proteins, and then carry out an in-depth and systematic mechanism. And ultimately to obtain a highly effective brain targeting HIV entry inhibitor, to provide a new type of drug for the treatment of brain HIV infection and eliminate the HIV brain reservoir.

近年来，以HIV包膜蛋白gp41为靶点的进入（融合）抑制剂成为艾滋病药物研究领域的热点之一。因血脑屏障(BBB)的存在，传统HAART治疗药物无法有效入脑，导致了HIV脑潜伏库的形成。为清除HIV脑潜伏库，进而实现艾滋病的功能性治愈，临床上急需一类能穿透BBB、毒副作用低的抗HIV药物。Angiopep-2是一段能与BBB上高表达的低密度脂蛋白受体相关蛋白(LRP)结合进而入脑的多肽，已成功递送了多种药物入脑。本课题拟通过不同长度和类型的连接子（linker）连接Angiopep-2及最新一代的多肽类HIV进入抑制剂T1144，进而使该进入抑制剂T1144获得脑靶向能力。本课题还将通过对linker进行优化，对候选蛋白的抗HIV活性及BBB穿透能力进行评价，进而开展深入而系统的机制研究。最终获得一种高效的脑靶向HIV进入抑制剂，为脑部HIV感染的治疗及脑潜伏库的清除提供一种新型药物。

脑是重要的HIV-1储存库之一，HAART疗法虽能最大限度抑制HIV-1的复制，却无法有效阻止HIV对中枢神经系统的感染。由于血脑屏障的存在，脑潜伏库的激活和脑部HIV-1感染的药物阻断成为HIV治疗的“shock and kill”策略的难点。因此，本课题构建一种能通过血脑屏障以阻断HIV对中枢神经系统感染的HIV多肽类进入抑制剂药物。本研究将多肽药物T1144与脑靶向多肽Angiopep-2通过不同长度的linker连接后进行融合表达。实验优选了连接子linker的长度、以及优选了HIV进入抑制剂活性部位T1144与靶头基团Angiopep-2在氨基端及羧基端的位置。通过构建HIV细胞-细胞融合模型及假病毒感染模型，初步分析了候选药物的抗HIV活性，发现T1144位于N端的结构（TLnA）更有利于保持T1144的抗病毒活性。并通过FN-page验证T1144不论在N端还是C端均有抑制HIV gp41 六螺旋6-HB形成的能力。在小鼠模型中，初步检测了候选药物TL6A具备穿透血脑屏障的能力。同时对候选药物的细胞毒性进行了分析。通过后续进一步的优化，候选多肽有望开发成一种新型HIV进入抑制剂药物。

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