Resin-Bound Crypto-Thioester for Native Chemical Ligation

The resin-bound <i>N</i>-sulfanylethylanilide (SEAlide) peptide was found to function as a crypto-thioester peptide. Exposure of the peptide resin to an aqueous solution under neutral conditions in the presence of thiols affords thioesters without accompanying racemization of C-terminal amino acids. Furthermore, the resin-bound SEAlide peptides react with N-terminal cysteinyl peptides in the absence of phosphate salts to afford ligated products, whereas soluble SEAlide peptides do not. This unexpected difference in reactivity of the SEAlide peptides allows for a one-pot/three-fragment ligation using resin-bound and unbound peptides

A Dual Arylboronic Acid–Aminothiourea Catalytic System for the Asymmetric Intramolecular Hetero-Michael Reaction of α,β‑Unsaturated Carboxylic Acids

A bifunctional aminoboronic acid has been used to facilitate for the first time the intramolecular aza- and oxa-Michael reactions of α,β-unsaturated carboxylic acids. The combination of an arylboronic acid with a chiral aminothiourea allowed for these reactions to proceed successfully in an enantioselective manner to afford the desired heterocycles in high yields and ee’s (up to 96% ee). The overall utility of this dual catalytic system was demonstrated by a one-pot enantioselective synthesis of (+)-erythrococcamide B, which proceeded via sequential Michael and amidation reactions

Chemically Programmed Antibodies As HIV‑1 Attachment Inhibitors

Herein, we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. <i>N</i>-Acyl-β-lactam derivatives of two previously described molecules BMS-378806 and BMS-488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides

One-Pot/Sequential Native Chemical Ligation Using Photocaged Crypto-thioester

A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable <i>S</i>-protection on an <i>N</i>-sulfanyl­ethyl­aniline moiety. Removal of the <i>S</i>-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation

Development of an Intein-Inspired Amide Cleavage Chemical Device

A photoresponsive amide cleavage device was developed based on the asparagine imidation-mediated cleavage of peptide bonds during intein-mediated protein splicing. The chemical environment of the protein splicing process was mimicked by the incorporation of geminal dimethyl groups and a secondary amine unit in asparagine scaffold. Furthermore, the resulting photoresponsive device could induce the phototriggered cleavage of an amide bond by the protection of the secondary amine unit with an <i>o</i>-nitrobenzyloxycarbonyl group

Development of an Anilide-Type Scaffold for the Thioester Precursor <i>N</i>‑Sulfanylethylcoumarinyl Amide

<i>N</i>-Sulfanylethylcoumarinyl amide (SECmide) peptide, which was initially developed for use in the fluorescence-guided detection of promoters of N–S acyl transfer, was successfully applied to a facile and side reaction-free protocol for N–S acyl-transfer-mediated synthesis of peptide thioesters. Additionally, 4-mercaptobenzylphosphonic acid (MBPA) was proven to be a useful catalyst for the SECmide or <i>N</i>-sulfanylethylanilide (SEAlide)-mediated NCL reaction

Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1‑Selective Inactivators

Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide <b>3</b>, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide <b>3</b> is a mechanism-based LSD1 inhibitor. Furthermore, peptides <b>37</b> and <b>38</b>, which consist of cell-membrane-permeable oligoarginine conjugated with peptide <b>3</b>, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide <b>37</b> decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1