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VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis

机译：VX-166：新型有效的小分子半胱天冬酶抑制剂，可作为脓毒症的潜在疗法

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IntroductionPrevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.MethodsVX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP).ResultsVX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected.ConclusionsOur studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
机译：前言有人提出通过胱天蛋白酶抑制来预防淋巴细胞凋亡是败血症的一种新型治疗方法。然而，尚未明确证明胱天蛋白酶抑制剂在感染后给药时可改善败血症模型的存活率。同样，人们担心半胱天冬酶抑制剂可能会抑制免疫反应。在此，我们将宽广的半胱天冬酶抑制剂VX-166表征为败血症的一种新型潜在治疗方法。方法VX-166在许多酶促和细胞分析中得到了研究。然后通过盲肠结扎和穿刺（CLP）在小鼠内毒素休克模型（脂多糖（LPS），20 mg / kg静脉内）和10 d大鼠脓毒症小鼠模型中测试了该化合物。结果VX-166显示出有效的抗凋亡作用体外活性并抑制白介素（IL）-1beta和IL-18的释放。在LPS模型中，LPS后0、4、8和12 h施用的VX-166以剂量依赖性方式显着提高了生存率（P <0.0028）。在CLP模型中，用微渗透泵连续给药的VX-166在受侵害后3小时给药后可显着提高生存率（40％至92％，P = 0.009）。 CLP后8小时给药时，VX-166将生存率从40％提高到66％（P = 0.19）。通过流式细胞术确定，CLP模型中的作用模式研究证实VX-166显着抑制胸腺萎缩和淋巴细胞凋亡（P <0.01）。 VX-166降低血浆内毒素水平（P <0.05），表明细菌从血流中的清除率提高。 IL-1beta体内释放或体外T细胞活化受到中等程度的影响。结论我们的研究增加了在脓毒症中使用caspase抑制剂的案例。 VX-166本身有望作为治疗男性败血症的疗法。

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