Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Article Article scientifique Article Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors eng 2021 author Lim Bumhee 936049 author Cheng Yangyang 876922 author Kato Takehiro 916166 author Pham Anh Tuan 880527 author Le Du Eliott author Mishra Abhaya Kumar author Grinhagena Elija author Moreau Dimitri 751508 author Sakai Naomi 0000-0002-9460-1944 131140 author Waser Jérôme 787238 author Matile Stefan 0000-0002-8537-8349 129654 1-9 10.1002/hlca.202100085 0018-019X https://onlinelibrary.wiley.com/doi/10.1002/hlca.202100085 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. Dewey 540 36 Département de chimie organique 141 39 Département de biochimie 144 false 761 Groupe Matile Helvetica Chimica Acta 104 e2100085 91f5c87a-3d72-4a37-823b-6e43f56e2bbb Article (Published version) Public hlca.202100085.pdf 10291644 application/pdf CC BY openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique Faculté des sciences / Section de chimie et biochimie / Département de biochimie

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Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors	Helvetica Chimica Acta			2021	272	442

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Waser, Jérôme