Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell activation.
Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell activation.
复制标题
走向去个性化阿巴卡韦疗法：化学修饰消除了 HLA-B*57 : 01 限制的 CD8 T 细胞激活。
DOI：
10.1097/qad.0000000000000867
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Naisbitt DJ
中科院分区：
文献类型：
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作者：
Naisbitt DJ
目的：在携带人类白细胞抗原（HLA）-B* 57：01的个体中，暴露于阿巴卡韦与T细胞介导的超敏反应相关。为了激活T细胞，阿巴卡韦直接与内源性HLA-B* 57：01和抗原呈递细胞表面上表达的HLA-B* 57：01相互作用。我们已经研究了阿巴卡韦的化学修饰是否可以产生一种具有抗病毒活性的分子，该分子不结合HLA-B* 57：01并激活T细胞。设计：使用来自表达HLA-B* 57：01的人类供体的样本的跨学科实验室研究。研究人员对类似物结构和建模数据一无所知。方法：合成了16个6-氨基取代的阿巴卡韦类似物。完成计算对接研究以预测HLA-B* 57：01内类似物结合的能力。产生阿巴卡韦响应性CD 8+克隆以研究HLA-B* 57：01类似物结合与T细胞活化之间的关联。抗病毒活性和对proliferation.Results的类似物的直接抑制作用进行了评估：主要组织相容性复合物I类限制性CD 8+克隆增殖和分泌IFNγ阿巴卡韦结合表面和内源性HLA-B* 57：01。几个类似物保留抗病毒活性，并没有表现出明显的抑制作用的增殖，但表现出高度不同的抗原驱动的T细胞反应。例如，阿巴卡韦和N-丙基阿巴卡韦在激活克隆方面同样有效，而密切相关的类似物N-异丙基和N-甲基异丙基阿巴卡韦缺乏T细胞活性。对接阿巴卡韦类似物HLA-B* 57：01揭示了药物蛋白结合和T细胞responsibility.Conclusion之间的定量关系：这些研究表明，不需要的T细胞活性阿巴卡韦可以消除，同时保持有利的抗病毒档案。计算机模拟模型提供了一种工具，可以帮助设计更安全的抗病毒药，这些抗病毒药可能不需要个性化的药物治疗方法。
Objective:Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B* 57: 01. To activate T cells, abacavir interacts directly with endogenous HLA-B* 57: 01 and HLA-B* 57: 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B* 57: 01 and activate T cells.Design:An interdisciplinary laboratory study using samples from human donors expressing HLA-B* 57: 01. Researchers were blinded to the analogue structures and modelling data.Methods:Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B* 57: 01. Abacavir-responsive CD8+ clones were generated to study the association between HLA-B* 57: 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed.Results:Major histocompatibility complex class I-restricted CD8+ clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B* 57: 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B* 57: 01 revealed a quantitative relationship between drug–protein binding and the T-cell response.Conclusion:These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.