Inhibitors of thiol-mediated uptake,Chemical Science

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Inhibitors of thiol-mediated uptake
Chemical Science ( IF 7.6 ) Pub Date : 2020-11-18 , DOI: 10.1039/d0sc05447j
Yangyang Cheng ₁ , Anh-Tuan Pham ₁ , Takehiro Kato ₁ , Bumhee Lim ₁ , Dimitri Moreau ₁ , Javier López-Andarias ₁ , Lili Zong ₁ , Naomi Sakai ₁ , Stefan Matile ₁

Affiliation

Ellman's reagent has caused substantial confusion and concern as a probe for thiol-mediated uptake because it is the only established inhibitor available but works neither efficiently nor reliably. Here we use fluorescent cyclic oligochalcogenides that enter cells by thiol-mediated uptake to systematically screen for more potent inhibitors, including epidithiodiketopiperazines, benzopolysulfanes, disulfide-bridged γ-turned peptides, heteroaromatic sulfones and cyclic thiosulfonates, thiosulfinates and disulfides. With nanomolar activity, the best inhibitors identified are more than 5000 times better than Ellman's reagent. Different activities found with different reporters reveal thiol-mediated uptake as a complex multitarget process. Preliminary results on the inhibition of the cellular uptake of pseudo-lentivectors expressing SARS-CoV-2 spike protein do not exclude potential of efficient inhibitors of thiol-mediated uptake for the development of new antivirals.

中文翻译：

硫醇介导的摄取抑制剂

Ellman 的试剂作为硫醇介导摄取的探针引起了极大的混乱和关注，因为它是唯一可用的已确定抑制剂，但既不有效也不可靠。在这里，我们使用通过硫醇介导的摄取进入细胞的荧光环状寡硫属化物系统地筛选更有效的抑制剂，包括桥二硫二酮哌嗪、苯并聚硫烷、二硫键桥接的 γ 转肽、杂芳族砜和环状硫代磺酸盐、硫代亚磺酸盐和二硫化物。具有纳摩尔活性，鉴定出的最佳抑制剂比 Ellman 试剂好 5000 倍以上。不同记者发现的不同活动揭示了硫醇介导的摄取是一个复杂的多靶点过程。

更新日期：2020-11-18

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