近日，复旦大学姜世勃/陆路研究团队与北卡罗莱纳大学教堂山分校的苏立山教授合作，利用IgG结合肽（IBP）策略，研发了能够高效抑制HIV-1感染的长效多肽类融合抑制剂IBP-CP24，其可以单独或者与广谱中和抗体联用来预防和治疗HIV-1的感染。目前该研究成果于2019年12月5日以 “IgG Fc-binding Motif-conjugated HIV-1 Fusion Inhibitor Exhibits Improved Potency and in vivo Half-life: Potential Application in Combination with Broad Neutralizing Antibodies”为题在线发表在PLoS Pathogens。该论文的研究成果同时也被PLoS Pathogens重点报道（selected to be highlighted with a PLOS Pathogenspress release）。
美国Trimeris制药公司在购买了姜世勃的美国发明专利之后与罗氏制药公司联合开发出来的第一个HIV多肽类融合抑制剂 - 恩夫韦肽（又称T20）已在临床上应用了16年。但由于其存在着半衰期较短及易产生抗药株的缺点，其在临床上的应用受到了限制。因此，开发抗HIV-1的多肽类入侵抑制剂是该研究领域急需解决的关键性科学问题。
为解决该关键科学问题，研究人员将来源于HIV-1 CHR的多肽CP24与能够和人类免疫球蛋白Fc可逆性结合的IBP基序融合来延长其半衰期（ 图1）。该研究团队发现将IBP与CP24的N端连接后，其在恒河猴体内的半衰期与CP24相比延长了约26倍（ 图2A）。同时该研究团队利用北卡罗莱纳大学教堂山分校苏立山教授团队的人源化小鼠模型进一步评估IBP-CP24在体内的治疗效果，结果显示IBP-CP24在慢性HIV-1感染的人源化小鼠模型上具有显著的治疗效果（ 图2B）。
图1. 抗HIV-1长效多肽的设计
图2. IBP-CP24比CP24具有更长的半衰期和更强的抗HIV-1活性。
研究团队还评估了长效多肽IBP-CP24与广谱中和抗体N6、VRC07和10E8联合应用对抑制HIV-1感染的效应，研究结果显示IBP-CP24与广谱中和抗体（如N6）联合使用可以更有效地抗击HIV，达到“双重打击”或“一箭双雕”的效果（图3）。
图3. IBP-CP24与中和抗体在体外联合的抗HIV-1策略。
因为N6抗体作为携带IBP-CP24多肽的生物导弹， 它对准一个病毒颗粒的gp120进行第一次打击，再通过其释放的IBP-CP24对准该病毒颗粒的gp41进行第二次打击，双重作用该病毒（即“双重打击”）。另外，N6抗体通过靶向一个病毒颗粒的gp120进行打击，再利用其释放的 IBP-CP24多肽通过靶向另一个病毒颗粒的gp41进行打击（即“一箭双雕”）。综上结果表明IBP-CP24有望被开发成为一种新型的长效HIV-1融合抑制剂多肽，可以单独或者与中和抗体联用来治疗或预防HIV-1的感染，可望能大大降低抗体和多肽的使用剂量及治疗费用。
复旦大学的博士生毕稳稳和博士后徐巍为本文的共同第一作者，复旦大学姜世勃教授和陆路研究员，美国北卡罗莱纳大学教堂山分校的苏立山教授为本文的共同通讯作者。本研究得到了中国医学科学院比较医学中心秦川教授和薛婧博士的大力支持与帮助；受到了来自于国家自然科学基金重点和面上项目、国家十三五传染病重大专项和美国NIH等基金的资助。
Abstract
The clinical application of conventional peptide drugs, such as the HIV-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. To overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24, by fusing it with the human IgG Fc-binding peptide (IBP). The newly engineered peptide IBP-CP24 exhibited potent and broad anti-HIV-1 activity with IC50 values ranging from 0.2 to 173.7 nM for inhibiting a broad spectrum of HIV-1 strains with different subtypes and tropisms, including those resistant to enfuvirtide. Most importantly, its half-life in the plasma of rhesus monkeys was 46.1 h, about 26- and 14-fold longer than that of CP24 (t1/2 = 1.7 h) and enfuvirtide (t1/2 = 3 h), respectively. IBP-CP24 intravenously administered in rhesus monkeys could not induce significant IBP-CP24-specific antibody response and it showed no obvious in vitro or in vivotoxicity. In the prophylactic study, humanized mice pretreated with IBP-CP24 were protected from HIV-1 infection. As a therapeutic treatment, coadministration of IBP-CP24 and normal human IgG to humanized mice with chronic HIV-1 infection resulted in a significant decrease of plasma viremia. Combining IBP-CP24 with a broad neutralizing antibody (bNAb) targeting CD4-binding site (CD4bs) in gp120 or a membrane proximal external region (MPER) in gp41 exhibited synergistic effect, resulting in significant dose-reduction of the bNAb and IBP-CP24. These results suggest that IBP-CP24 has the potential to be further developed as a new HIV-1 fusion inhibitor-based, long-acting anti-HIV drug that can be used alone or in combination with a bNAb for treatment and prevention of HIV-1 infection.
Author summary
Enfuvirtide (T20) is the first US FDA-approved anti-HIV peptide drug. However, its clinical application is limited because of its short half-life and emergence of T20-resistant HIV strains. Here we developed a new strategy to prolong the half-life of a short anti-HIV peptide (CP24) by conjugating it with the human IgG Fc-binding peptide (IBP). IBP-CP24 exhibited potent and broad anti-HIV-1 activity and prolonged half-life, indicating its potential to be developed as a long-acting anti-HIV drug. Interestingly, combinational use of IBP-CP24 with a broad HIV neutralizing antibody, such as N6, showed synergistic anti-HIV-1 effect, suggesting that IBP-CP24 can be used together with N6 to treat HIV-1 infection because N6, as a biomissile carrying IBP-CP24, binds gp120 to make the first strike, and releases IBP-CP24 that binds gp41 to make the second strike to HIV-1. Therefore, combining IBP-CP24 with a bNAb may reduce the dose of the antibody and peptide, thus the cost of the treatment. 来源：中国病毒学（英文版） 本期编辑：Tony
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