Inhibitors of thiol-mediated uptake.

Yangyang Cheng,Lili Zong,Bumhee Lim,Dimitri Moreau,Takehiro Kato,Anh-Tuan Pham,Stefan Matile,Javier López-Andarias,Naomi Sakai

doi:10.1039/d0sc05447j

Abstract

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.

Highlights

We use fluorescent cyclic oligochalcogenides that enter cells by thiol-mediated uptake to systematically screen for more potent inhibitors, including epidithiodiketopiperazines, benzopolysulfanes, disulfide-bridged gturned peptides, heteroaromatic sulfones and cyclic thiosulfonates, thiosulfinates and disulfides
Different activities found with different reporters reveal thiol-mediated uptake as a complex multitarget process
With increasingly unorthodox cyclic oligochalcogenides (COCs) chemistry, from strained disul des[7,8] and diselenides[9] to adaptive dynamic covalent networks produced by polysulfanes,[10] uptake activities steadily increased. Their high activities suggested that the same, or complementary, COCs could function as powerful inhibitors of thiol-mediated uptake that might perhaps lead to antivirals

Summary

Introduction

Different activities found with different reporters reveal thiol-mediated uptake as a complex multitarget process. Their high activities suggested that the same, or complementary, COCs could function as powerful inhibitors of thiol-mediated uptake that might perhaps lead to antivirals.

Results

Conclusion