查看胞壁酰二肽及其衍生物:免疫疾病和癌症治疗中的肽佐剂的源代码
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胞壁酰二肽及其衍生物:免疫疾病和癌症治疗中的肽佐剂
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=== 生物活性 === MDP 的佐剂活性 佐剂是一种增强化合物引起的刺激反应的药物,其本身几乎没有直接影响。MDP 和其他多肽是有效的佐剂,可用于提高药物和疫苗的效力。它们通过增强细胞粘附和抗原呈递所需的表达表面标志物来做到这一点,从而增加吞噬细胞和抗微生物活性,并促进抗体介导的细胞毒性[9-12,13,14]。此外,MDP 和其他多肽(三肽和二糖三肽和四肽)通过增加 IFN-γ和其他细胞因子的产生来诱导免疫反应,刺激淋巴细胞的分化和增殖,淋巴细胞是白细胞的一个子集,在人体抵御外来入侵者方面发挥着不可或缺的作用[15‒17]。MDP在体外和体内也被证明是细胞启动所需的最小结构,其中预暴露于肽可增强对后期攻击的免疫反应[18,19]。D-异谷氨酰胺残基被 D-谷氨酰胺、D-谷氨酸或 D-异天冬酰胺取代的类似物的启动作用降低,而用 L-谷氨酸、L-谷氨酰胺或 L-异谷氨酰胺取代的类似物则失活[15,19]。此外,多肽与其他配体表现出很强的协同作用,它们一起引起比单独使用每种配体更大的免疫反应。例如,MDP 已被证明与 LPS(脂多糖)具有协同作用,LPS 存在于革兰氏阴性菌的外膜中,并被细胞表面受体 Toll 样受体-4 (TLR4) 识别。在体外的人类原代细胞(包括全血、外周血单核细胞(PBMC)、纯化的单核细胞以及各种人单核细胞和啮齿动物细胞系)以及厌食症大鼠模型中观察到这种协同作用[20‒28]。 Adjuvant activity of MDP An adjuvant is an agent that enhances the stimulatory response elicited by compounds having few if any direct effects on their own. MDP and other muropeptides are effective adjuvants and may be used for boosting the potency of drugs and vaccines. They do so by enhancing the expression surface markers necessary for cell adhesion and antigen presentation, thereby increasing phagocytic and anti-microbial activity and facilitating antibody-mediated cytotoxicity [9–12, 13, 14]. Moreover, MDP and other muropeptides (tripeptides and disaccharide tri- and tetrapeptides) induce immune responses by increasing IFN-γ and other cytokine production, stimulating the differentiation and proliferation of lymphocytes, a subset of white blood cells that play and integral role in the body’s defense against foreign intruders [15–17]. MDP has also been shown in vitro and in vivo to be the minimal structure required for the priming of cells, where pre-exposure to the peptide augments immune responses to a later challenge [18, 19]. Analogues where the D-isoglutamine residue is replaced by D-glutamine, D-glutamic acid, or D-isoasparagine have a reduced priming effect, whereas analogues replaced with L-glutamic acid, L-glutamine, or L-isoglutamine are inactive [15, 19]. Furthermore, muropeptides express strong synergy with other ligands, where together they elicit a greater immune response than each alone would. For example, MDP has been shown to have a synergistic effect with LPS (lipopolysaccharides), found in the outer membrane of Gram-negative bacteria and recognized by the cell-surface receptor Toll-like receptor-4 (TLR4). This synergy was observed in vitro in human primary cells, including whole blood, peripheral blood mononuclear cells (PBMCs), purified monocytes, and various human monocytic and rodent cell lines, and in vivo in a rat model for anorexia [20–28]. MDP 用于治疗癌症和其他疾病 MDP 及其衍生物具有多种临床用途和治疗潜力。例如,[https://www.medchemexpress.cn/murabutide.html 莫拉布胺](Murabutide, MB)是一种源自 MDP 的合成免疫调节剂,可增强对细菌和病毒感染的非特异性抵抗力,而不会发烧,并降低小鼠 LPS 的致死率[29‒32]。在小鼠模型中,它还被观察到与抗病毒和抗炎细胞因子(如 IFN-α)协同作用,并增加 IFN-α 和 IL-2 的抗肿瘤作用[33,34]。最重要的是,MB 调节细胞因子的产生,而不会显著诱导促炎介质[35]。研究表明,将其与IL-2联合注射到携带 Meth-A 肉瘤的小鼠体内,在 70% 的治疗小鼠中,肿瘤显著抑制和肿瘤完全消退[33]。MB 还被证明可显著抑制急性感染的单核细胞来源的巨噬细胞和树突状细胞中的 HIV-1复制[36]。已经努力开发其他类似的 MDP 衍生药物。由脂质体包封的免疫调节剂(MTP-PE,一种 MDP 衍生物)激活的巨噬细胞或由 PolyG(一种 10 聚体聚鸟胍酸)偶联的 MDP 已导致杀瘤活性[37,38]。另一种试剂是与 MDP 偶联的紫杉醇(紫杉醇®),不仅具有抗肿瘤活性,还具有免疫增强作用[39]。 MDP for therapies of cancer and other diseases MDP and its derivatives have a variety of clinical uses and therapeutic potential. Murabutide (MB), for example, is a synthetic immunomodulator derived from MDP that enhances non-specific resistance to bacterial and viral infections without fever and decreases the lethality of LPS in mice [29–32]. It has also been observed to synergize with antiviral and anti-inflammatory cytokines such as IFN-α as well as increase the anti-tumor effects of IFN-α and IL-2 in mouse models [33, 34]. Most importantly, MB regulates cytokine production without dramatically inducing proinflammatory mediators [35]. Studies have shown that injecting it in combination with IL-2 into Meth-A sarcoma-bearing mice resulted in significant tumor inhibition and complete tumor regression in 70% of the treated mice [33]. MB has also been shown to significantly inhibit HIV-1 replication in acutely infected monocyte-derived macrophages and dendritic cells [36]. Efforts have already been made to develop other similarly MDP-derived drugs. Macrophages activated by a liposome-encapsulated immunomodulator (MTP-PE, a MDP-derivative) or MDP conjugated by PolyG (a 10-mer polyguanylic acid), have resulted in tumoricidal activity [37, 38]. Another reagent, Paclitaxel (Taxol®) conjugated to MDP, has not only antitumor activity but also immunoenhancement effects [39]. <br>
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