Wild C T, Shugars D C, Greenwell T K, McDanal C B, Matthews T J
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9770-4. doi: 10.1073/pnas.91.21.9770.
To define the role of the human immunodeficiency virus type 1 (HIV-1) envelope proteins in virus infection, a series of peptides were synthesized based on various regions of the HIV-1 transmembrane protein gp41. One of these peptides, DP-178, corresponding to a region predictive of alpha-helical secondary structure (residues 643-678 of the HIV-1LAI isolate), has been identified as a potent antiviral agent. This peptide consistently blocked 100% of virus-mediated cell-cell fusion at < 5 ng/ml (IC90 approximately 1.5 ng/ml) and gave an approximately 10 times reduction in infectious titer of cell-free virus at approximately 80 ng/ml. The inhibitory activity was observed at peptide concentrations approximately 10(4) to 10(5) times lower than those at which cytotoxicity and cytostasis were detected. Peptide-mediated inhibition is HIV-1 specific in that approximately 10(2) to 10(3) times more peptide was required for inhibition of a human immunodeficiency virus type 2 isolate. Further experiments showed that DP-178 exhibited antiviral activity against both prototypic and primary HIV-1 isolates. As shown by PCR analysis of newly synthesized proviral DNA, DP-178 blocks an early step in the virus life cycle prior to reverse transcription. Finally, we discuss possible mechanisms by which DP-178 may exert its inhibitory activity.
为了确定人类免疫缺陷病毒1型（HIV-1）包膜蛋白在病毒感染中的作用，基于HIV-1跨膜蛋白gp41的不同区域合成了一系列肽段。其中一种肽段DP-178，对应于预测具有α螺旋二级结构的区域（HIV-1 LAI分离株的643-678位氨基酸残基），已被鉴定为一种有效的抗病毒剂。该肽段在浓度低于5 ng/ml时能持续阻断100%的病毒介导的细胞-细胞融合（IC90约为1.5 ng/ml），并在约80 ng/ml时使无细胞病毒的感染滴度降低约10倍。在肽段浓度比检测到细胞毒性和细胞生长抑制的浓度低约10^4至10^5倍时仍观察到抑制活性。肽段介导的抑制具有HIV-1特异性，因为抑制人类免疫缺陷病毒2型分离株所需的肽段量要多约10^2至10^3倍。进一步的实验表明，DP-178对原型和原发性HIV-1分离株均表现出抗病毒活性。如新合成的前病毒DNA的PCR分析所示，DP-178在逆转录之前阻断病毒生命周期的早期步骤。最后，我们讨论了DP-178可能发挥其抑制活性的潜在机制。
