A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.
A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.
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DOI：
10.1371/journal.pone.0041235
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wahren B
中科院分区：
文献类型：
--
作者：
Chang CH;Hinkula J;Loo M;Falkeborn T;Li R;Cardillo TM;Rossi EA;Goldenberg DM;Wahren B
我们构建了新的HIV-1融合抑制剂，可以克服目前恩夫韦肽的局限性，恩夫韦肽是这类药物中的第一种。通过Dock-and-Lock（DNL）技术生成的三种原型包含四个拷贝的恩夫韦肽，这些恩夫韦肽位点特异性连接到不同人源化单克隆抗体的Fc端，在体外有效中和HIV-1的原代分离株（R5-嗜性和X4-嗜性）以及T细胞适应株。所有三种原型都显示出亚纳摩尔范围内的EC 50值，其比恩夫韦肽低10至100倍，并且无论组成型抗体是否靶向HIV-1都可达到。在细胞间病毒抑制试验中，通过测量在用100 nM SAHA（辛二酰苯胺异羟肟酸）进行病毒活化后30天内，这些缀合物抑制HIV-1 LAI从感染的人外周血单核细胞扩散至Jurkat T细胞的效力，也证明了这些缀合物清除潜伏感染细胞的潜力。IgG样半衰期与亲本抗体的半衰期无显著差异，如72 h时小鼠中一种原型的平均血清浓度所示。这些令人鼓舞的结果提供了通过经由重组产生的、自组装的模块将另外的感兴趣的抗体与替代的HIV抑制剂偶联来开发进一步的新型抗HIV剂的理论基础。
We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.
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DOI：
10.1073/pnas.94.5.1925
发表时间：
1997-03-04
影响因子：
11.1
作者：
Bleul, CC;Wu, LJ;Mackay, CR
通讯作者：
Mackay, CR
DOI：
10.1126/science.1213782
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diskin R;Scheid JF;Marcovecchio PM;West AP Jr;Klein F;Gao H;Gnanapragasam PN;Abadir A;Seaman MS;Nussenzweig MC;Bjorkman PJ
通讯作者：
Bjorkman PJ
DOI：
10.1073/pnas.0805098105
发表时间：
2008-11-18
影响因子：
11.1
作者：
Gaertner, Hubert;Cerini, Fabrice;Hartley, Oliver
通讯作者：
Hartley, Oliver
影响因子：
4.1
作者：
Makinson, Alain;Reynes, Jacques
通讯作者：
Reynes, Jacques
影响因子：
4.7
作者：
Chang, Chien-Hsing;Rossi, Edmund A.;Goldenberg, David M.
通讯作者：
Goldenberg, David M.