7 research outputs found
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>-sulfanylÂethylÂaniline 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