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Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides.

ABSTRACT: Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As), and the development of solid-phase synthesis conditions for their incorporation into peptides. Monomeric and dimeric α-helical peptides are synthesised with varying degrees of Q4A substitution and their structures examined using biophysical methods. Both enantiomers of the Q4As are tolerated in folded monomeric and oligomeric α-helical peptides, with the (R)-enantiomer slightly more so than the (S).

SUBMITTER: Leonard DJ

PROVIDER: S-EPMC8278958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters.

Project description:A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C-C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

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Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function

Project description:Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Tregs) remains a complicating factor to their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg deletional strategies, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable, non-toxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg function, and lead to Treg gene expression changes in vivo consistent with Foxp3 dysfunction.

2022-09-29 | GSE201116 | GEO

Unifying structural signature of eukaryotic α-helical host defense peptides.

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Development of Bifunctional, Raman Active Diyne-Girder Stapled α-Helical Peptides.

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Oligoorganogermanes: Interplay between Aryl and Trimethylsilyl Substituents.

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Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents.

Project description:This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.

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Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling.

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| S-EPMC9828748 | biostudies-literature

Contemporary strategies for the stabilization of peptides in the alpha-helical conformation.

Project description:Herein we review contemporary synthetic and protein design strategies to stabilize the alpha-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the use of hydrocarbon bridges to either crosslink side chains of specific residues or mimic intramolecular hydrogen bonds with carbon-carbon bonds. The resulting hydrocarbon-stapled and hydrogen bond surrogate alpha-helices provide unique synthetic ligands for targeting biomolecules. In the protein design realm, several classes of miniature proteins that display stable helical domains have been engineered and manipulated with powerful in vitro selection technologies to yield libraries of sequences that retain their helical folds. Rational re-design of these scaffolds provide distinctive reagents for the modulation of protein-protein interactions.

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Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity.

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