Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide
Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide
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DOI：
10.1073/pnas.0805098105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Hartley, Oliver
中科院分区：
文献类型：
--
作者：
Gaertner, Hubert;Cerini, Fabrice;Hartley, Oliver
迫切需要在发展中国家采用新的预防战略，以遏制艾滋病毒/艾滋病在全世界的流行。N-末端修饰的趋化因子PSC-RANTES是一种针对R5-嗜性HIV-1毒株的高效进入抑制剂，其抑制机制涉及HIV辅助受体CCR 5的长期细胞内隔离。PSC-RANTES在阴道HIV传播的猕猴模型中局部应用时具有完全保护性，但其具有与进一步开发相关的2个潜在缺点：化学合成的要求增加了生产成本，并且其强CCR 5激动剂活性可能诱导局部炎症。因此，优选找到保留PSC-RANTES的高效力但缺乏其激动剂活性的重组类似物。使用基于噬菌体展示的策略，我们着手发现仅含有天然氨基酸的PSC-RANTES类似物。我们寻求保留PSC-RANTES的效力和抑制机制的分子，同时试图将CCR 5信号传导降低到尽可能低的水平。我们鉴定了3种类似物，它们都表现出与PSC-RANTES相当的体外抗HIV-1效力。第一种，6P 4-RANTES，类似于PSC-RANTES，因为它是一种强激动剂，诱导CCR 5的延长的细胞内隔离。第二种是5 P12-RANTES，没有可检测到的G蛋白相关信号传导活性，也不会引起受体螯合。第三，5 P14-RANTES，诱导显着水平的CCR 5内化没有可检测的G蛋白相关的信号传导活性。这3种分子代表了进一步开发作为局部HIV预防策略的有希望的候选物。
New prevention strategies for use in developing countries are urgently needed to curb the worldwide HIV/AIDS epidemic. The N-terminally modified chemokine PSC-RANTES is a highly potent entry inhibitor against R5-tropic HIV-1 strains, with an inhibitory mechanism involving long-term intracellular sequestration of the HIV coreceptor, CCR5. PSC-RANTES is fully protective when applied topically in a macaque model of vaginal HIV transmission, but it has 2 potential disadvantages related to further development: the requirement for chemical synthesis adds to production costs, and its strong CCR5 agonist activity might induce local inflammation. It would thus be preferable to find a recombinant analogue that retained the high potency of PSC-RANTES but lacked its agonist activity. Using a strategy based on phage display, we set out to discover PSC-RANTES analogs that contain only natural amino acids. We sought molecules that retain the potency and inhibitory mechanism of PSC-RANTES, while trying to reduce CCR5 signaling to as low a level as possible. We identified 3 analogues, all of which exhibit in vitro potency against HIV-1 comparable to that of PSC-RANTES. The first, 6P4-RANTES, resembles PSC-RANTES in that it is a strong agonist that induces prolonged intracellular sequestration of CCR5. The second, 5P12-RANTES, has no detectable G protein-linked signaling activity and does not bring about receptor sequestration. The third, 5P14-RANTES, induces significant levels of CCR5 internalization without detectable G protein-linked signaling activity. These 3 molecules represent promising candidates for further development as topical HIV prevention strategies.