Abhaya Kumar Mishra

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Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water

Durga Prasada Rao Hari, Abhaya Kumar Mishra, Romain Gaëtan Tessier, Jérôme Waser

We report the functionalization of cysteine residues with lipophilic alkynes bearing a silyl group or an alkyl chain using amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions were carried out in buffer (pH 6 to 9), without organic co-solvent or removal of oxygen, either at 37 degrees C or room temperature. The transformation led to a significant increase of peptide lipophilicity and worked for aromatic thiols, homocysteine, cysteine, and peptides containing 4 to 18 amino acids. His(6)-Cys-Ubiquitin was also alkynylated under physiological conditions. Under acidic conditions, the thioalkynes were converted into thioesters, which could be cleaved in the presence of hydroxylamine.

2021

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Elija Grinhagena, Eliott Hugo Joran Le Du, Stefan Matile, Abhaya Kumar Mishra, Jérôme Waser

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.

2021

Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Solar and Visible Light Assisted Peptide Synthesis

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water

Solar and Visible Light Assisted Peptide Synthesis