Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals.

中文翻译：

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用不可逆共价抑制剂抑制硫醇介导的摄取

硫醇介导的摄取正在成为渗透细胞的首选方法。本研究侧重于硫醇介导的摄取的不可逆共价抑制剂。迄今为止最大的高价碘试剂集合的高内涵高通量筛选提供了比Ellman试剂活性高 250 倍以上的抑制剂，并与最好的动态共价抑制剂相媲美。与其他不可逆试剂的比较表明，一系列内的抑制遵循反应性，而跨系列的抑制则偏离反应性。这些趋势支持分子识别，除了动态共价交换，显着有助于硫醇介导的吸收。除了最好的高价碘试剂外，最强大的抑制剂是福山的 nosyl 保护基团和超级肉桂醛已被引入作为疼痛受体 TRPA1 的不可逆激活剂。考虑到几种病毒使用不同形式的硫醇介导的摄取进入细胞，因此鉴定新的硫醇介导摄取的不可逆抑制剂对于发现新的抗病毒药物具有普遍意义。