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Inhibition of Thiol-Mediated Uptake with Irreversible Covalent Inhibitors |
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| Authors: | Bumhee Lim Yangyang Cheng Takehiro Kato Anh-Tuan Pham Eliott Le Du Abhaya Kumar Mishra Elija Grinhagena Dimitri Moreau Naomi Sakai Jerome Waser Stefan Matile |
| Affiliation: | 1. Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland National Centre of Competence in Research (NCCR) Chemical Biology, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland These authors contributed equally to this study.;2. Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland National Centre of Competence in Research (NCCR) Chemical Biology, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland;3. Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Fédérale de Lausanne EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland;4. National Centre of Competence in Research (NCCR) Chemical Biology, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Fédérale de Lausanne EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland;5. National Centre of Competence in Research (NCCR) Chemical Biology, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland;6. Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland |
| Abstract: | 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. |
| Keywords: | antiviral agents hypervalent compounds hypervalent iodine reagents inhibitors nosyl protecting group thiol-mediated uptake TRPA1 pain receptor |