Ji Changhua, Kopetzki Erhard, Jekle Andreas, Stubenrauch Kay-Gunnar, Liu Xingrong, Zhang Jun, Rao Eileen, Schlothauer Tilman, Fischer Stephan, Cammack Nick, Heilek Gabrielle, Ries Stefan, Sankuratri Surya
Virology Diseases Area, Roche Palo Alto, Palo Alto, California 94304, USA.
J Biol Chem. 2009 Feb 20;284(8):5175-85. doi: 10.1074/jbc.M808745200. Epub 2008 Dec 19.
In this study, we describe a novel CD4-targeting bifunctional human immunodeficiency virus (HIV-1) fusion inhibitor (CD4-BFFI) that blocks HIV-1 entry by inhibiting both HIV-1 attachment and fusion and is highly potent against both R5 and X4 HIV-1 viruses in various antiviral assays, including peripheral blood mononuclear cell (PBMC) infection assays. Previously, we have reported a CCR5 antibody-based bifunctional HIV-1 fusion inhibitor (BFFI) that was highly active in blocking R5 HIV-1 infection but was ineffective against X4 viruses infecting human PBMCs (Kopetzki, E., Jekle, A., Ji, C., Rao, E., Zhang, J., Fischer, S., Cammack, N., Sankuratri, S., and Heilek, G. (2008) Virology J. 5, 56-65). CD4-BFFI, which consists of two HIV-1 fusion inhibitor (FI) T-651 variant peptides recombinantly fused to the Fc end of a humanized anti-CD4 monoclonal antibody, has demonstrated more than 100-fold greater antiviral activity than T-651 variant or the parental CD4 monoclonal antibody. Mechanistic studies revealed that CD4-BFFI primarily blocks the HIV-1-cell fusion step through its FI peptide moieties. The enhanced antiviral activity of CD4-BFFI is most likely due to avid binding of the bivalent FI peptides as well as the increased local concentration of CD4-BFFI via attachment to the target cell surface receptor CD4. In vivo pharmacokinetic studies demonstrated that CD4-BFFI was stable in monkey blood, and a dose of 10 mg/kg maintained serum concentrations greater than 2,000-fold over the IC(90) value for 7 days postdosing. This novel bifunctional inhibitor with improved potency and favorable pharmacokinetic properties may offer a novel approach for HIV-1 therapy.
在本研究中，我们描述了一种新型的靶向CD4的双功能人类免疫缺陷病毒（HIV-1）融合抑制剂（CD4-BFFI），它通过抑制HIV-1的附着和融合来阻断HIV-1进入，并且在包括外周血单核细胞（PBMC）感染试验在内的各种抗病毒试验中，对R5和X4 HIV-1病毒均具有高效力。此前，我们报道了一种基于CCR5抗体的双功能HIV-1融合抑制剂（BFFI），它在阻断R5 HIV-1感染方面具有高活性，但对感染人类PBMC的X4病毒无效（Kopetzki, E., Jekle, A., Ji, C., Rao, E., Zhang, J., Fischer, S., Cammack, N., Sankuratri, S., and Heilek, G. (2008) Virology J. 5, 56 - 65）。CD4-BFFI由两个HIV-1融合抑制剂（FI）T-651变体肽与一个人源化抗CD4单克隆抗体的Fc末端重组融合而成，其抗病毒活性比T-651变体或亲本CD4单克隆抗体高出100多倍。机制研究表明，CD4-BFFI主要通过其FI肽部分阻断HIV-1与细胞的融合步骤。CD4-BFFI抗病毒活性增强很可能是由于二价FI肽的avid结合以及通过附着于靶细胞表面受体CD4而增加的CD4-BFFI局部浓度。体内药代动力学研究表明，CD4-BFFI在猴血液中稳定，给药剂量为10 mg/kg时，给药后7天血清浓度维持在高于IC(90)值2000倍以上。这种具有更高效力和良好药代动力学特性的新型双功能抑制剂可能为HIV-1治疗提供一种新方法。
