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首页> 外文期刊>Clinical and Translational Allergy >Abacavir forms novel cross-linking abacavir protein adducts in patients
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Abacavir forms novel cross-linking abacavir protein adducts in patients

机译：阿巴卡韦在患者体内形成新型的交联阿巴卡韦蛋白加合物

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BackgroundAbacavir (ABC), a nucleoside-analogue reverse transcriptaseinhibitor, is associated with severe hypersensitivityreactions that involve the activation of CD8+ T cells in aHLA-B*57:01-restricted manner. Recent studies haveclaimed that non-covalent interactions of ABC withHLA-B*57:01 are responsible for the immunologicalreactions associated with ABC. However, the formationof haemoglobin-ABC aldehyde (ABCA) adducts inpatients exposed to ABC suggests that protein conjugationmight represent a pathway for antigen formation.MethodTo further characterize protein conjugation reactions,we used mass spectrometric methods to define ABCAmodifications of human serum albumin and glutathioneS-transferase Pi in vitro and in patients commencingABC therapy.ResultsABCA formed a novel intramolecular cross-linking adducton human serum albumin in patients and in vitro viaMichael addition, followed by nucleophilic adduction ofthe aldehyde with a neighbouring protein nucleophile.Adducts were detected on lysine, histidine, and cysteineresidues in subdomain IB of human serum albumin. Onlya cysteine adduct and a putative cross-linking adduct weredetected on glutathione S-transferase Pi. Modelling thedocking of ABCA with HLA B*57:01 confirmed thatABCA has a strong binding affinity when bound covalentlyto Ser116, a key residue with regards to recognition byABC-specific CD8+ T cells.ConclusionThese findings reveal that ABC forms novel types of haptensin all patients taking the drug. It is therefore vital thatthe immunological consequences of such haptenationpathways are explored in the in vitro models that havebeen used by various groups to define a new mechanismof drug hypersensitivity for ABC.
机译：背景算盘（ABC）是一种核苷类似物逆转录酶抑制剂，与严重的超敏反应有关，涉及以aHLA-B * 57：01限制的方式激活CD8 + T细胞。最近的研究声称，ABC与HLA-B * 57：01的非共价相互作用是与ABC相关的免疫反应的原因。然而，暴露于ABC的患者血红蛋白-ABC醛（ABCA）加合物的形成表明蛋白结合可能代表了抗原形成的途径。结果：ABCA在患者体内和体外通过Michael加成反应形成了一种新的分子内交联的人血清白蛋白，随后通过迈克尔加成反应将醛与相邻的蛋白质亲核试剂亲核加成，在赖氨酸，组氨酸和人血清白蛋白IB亚域IB中的半胱氨酸残基。在谷胱甘肽S-转移酶Pi上仅检测到半胱氨酸加合物和推定的交联加合物。用HLA B * 57：01对ABCA进行对接建模，证实了ABCA与Ser116共价结合时具有很强的结合亲和力，这是ABC特异性CD8 + T细胞识别的关键残基。毒品。因此，至关重要的是，在已被各种研究小组用于定义ABC药物超敏新机制的体外模型中，探索这种半抗原途径的免疫学后果。

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