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Inhibitors of thiol-mediated uptake

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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.

Graphical abstract: Inhibitors of thiol-mediated uptake

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Article information

01 Oct 2020
26 Oct 2020
First published
18 Nov 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021, Advance Article
Article type
Edge Article

Inhibitors of thiol-mediated uptake

Y. Cheng, A. Pham, T. Kato, B. Lim, D. Moreau, J. López-Andarias, L. Zong, N. Sakai and S. Matile, Chem. Sci., 2021, Advance Article , DOI: 10.1039/D0SC05447J

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