Pouillart P R, Audibert F M, Chedid L A, Lefrancier P L, Bahr G M
VACSYN S.A., Paris, France.
Int J Immunopharmacol. 1996 Mar;18(3):183-92. doi: 10.1016/0192-0561(96)00005-7.
The use of interferon-alpha (IFN-alpha) in the treatment of infectious diseases has shown limited efficacy and dose-limiting toxicity. We have selected safe immunomodulators of the muramyl peptide family with the potential of enhancing the efficacy of IFN-alpha without resulting in increased toxicity. One of these synthetic muramyl dipeptide (MDP) derivatives, namely murabutide which is in a clinical stage of development, has been recently found to synergize with IFN-alpha 2a in the selective induction of anti-inflammatory mediators and to enhance the biological activities of the therapeutic cytokine. The present study was performed to assess the antiviral activity of such muramyl peptides and a possible potentiation of the antiviral activity of IFN-alpha/beta by associated therapy using the classical assay of Encephalomyocarditis virus (EMCV) infection. In vitro, pretreatment of Moloney Sarcoma virus (MSV)-transformed cell line with MDP derivatives followed by treatment with IFN-alpha/beta showed a synergistic protection against the cytopathogenic effect of a subsequent EMCV infection. None of the MSV cultures could be protected by stimulation with muramyl peptides alone. In vivo, all of the muramyl peptide derivatives tested were found to be more potent than the parent molecule MDP in inducing protection against death or in the prolongation of the mean survival time of infected mice. Sequential administration of suboptimal doses of exogenous IFN-alpha/beta and muramyl peptides established a strong antiviral state and considerably improved the protective effect of the cytokine, frequently leading to an abortive infection. Our findings suggest that combination therapy with safe muramyl peptides and IFN-alpha/beta could constitute a highly effective and new regimen for the treatment of viral infections in humans.
α干扰素（IFN-α）用于治疗传染病时疗效有限且存在剂量限制性毒性。我们筛选了胞壁酰肽家族的安全免疫调节剂，它们有可能增强IFN-α的疗效而不增加毒性。这些合成胞壁酰二肽（MDP）衍生物之一，即处于临床开发阶段的murabutide，最近发现可与IFN-α 2a协同作用，选择性诱导抗炎介质，并增强治疗性细胞因子的生物活性。本研究旨在使用经典的脑心肌炎病毒（EMCV）感染检测方法，评估此类胞壁酰肽的抗病毒活性以及联合治疗对IFN-α/β抗病毒活性的可能增强作用。在体外，先用MDP衍生物预处理莫洛尼肉瘤病毒（MSV）转化的细胞系，然后用IFN-α/β处理，可对随后的EMCV感染的细胞病变效应产生协同保护作用。单独用胞壁酰肽刺激不能保护任何MSV培养物。在体内，所有测试的胞壁酰肽衍生物在诱导对死亡的保护或延长感染小鼠的平均存活时间方面都比母体分子MDP更有效。次优剂量的外源性IFN-α/β和胞壁酰肽的序贯给药建立了强大的抗病毒状态，并显著提高了细胞因子的保护作用，常常导致感染中止。我们的研究结果表明，安全的胞壁酰肽与IFN-α/β联合治疗可能构成一种治疗人类病毒感染的高效新方案。
