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Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors
Author(s) -
Lim Bumhee,
Cheng Yangyang,
Kato Takehiro,
Pham AnhTuan,
Le Du Eliott,
Mishra Abhaya Kumar,
Grinhagena Elija,
Moreau Dimitri,
Sakai Naomi,
Waser Jerome,
Matile Stefan
Publication year - 2021
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.202100085
Subject(s) - hypervalent molecule , chemistry , thiol , reagent , covalent bond , reactivity (psychology) , combinatorial chemistry , iodine , small molecule , biochemistry , organic chemistry , medicine , alternative medicine , pathology
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.