Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, 30172 Venice, Italy.
Department of Medicine, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
Chem Res Toxicol. 2022 Nov 21;35(11):2049-2058. doi: 10.1021/acs.chemrestox.2c00211. Epub 2022 Sep 23.
The current trend dealing with the production of per- and polyfluoroalkyl substances (PFASs) involves the shifting toward branched short-chain fluorinated compounds known as new-generation PFASs. A key aspect to be clarified, to address the adverse health effects associated with the exposure to PFASs, is their binding mode to human serum albumin (hSA), the most abundant protein in plasma. In this study, we investigated the interaction between hSA and two representative branched short-chain PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that both compounds bind hSA with affinities and stoichiometries lower than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition experiments using hSA-binding drugs with known site-selectivity revealed that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA. The crystal structure of hSA in complex with HPFO-DA unveiled the presence of two binding sites. The characterization and direct comparison of hSA interactions with new-generation PFASs may be key elements for the understanding of the toxicological impact of these compounds.
目前处理全氟和多氟烷基物质（PFASs）生产的趋势是转向称为新一代 PFASs 的支链短链氟化化合物。为了解决与 PFASs 暴露相关的不良健康影响，需要阐明的一个关键方面是它们与人血清白蛋白（hSA）的结合模式，hSA 是血浆中含量最丰富的蛋白质。在这项研究中，我们研究了 hSA 与两种代表性的支链短链 PFASs（即 HPFO-DA 和 C6O4）之间的相互作用。溶液中的研究表明，这两种化合物与 hSA 的结合亲和力和化学计量比都低于传统的长链全氟烷基化合物 PFOA。使用具有已知位点选择性的 hSA 结合药物进行的竞争实验表明，HPFO-DA 和 C6O4 都结合到位于亚结构域 IIIA 的口袋中。hSA 与 HPFO-DA 复合物的晶体结构揭示了存在两个结合位点。表征和直接比较 hSA 与新一代 PFASs 的相互作用可能是理解这些化合物的毒理学影响的关键因素。
