Structure‐Based Design of Bicyclic Helical Peptides That Target the Oncogene β‐Catenin DOI Creative Commons
Alejandro Yeste‐Vázquez, Felix M. Paulussen, Mathias Wendt

и другие.

Angewandte Chemie, Год журнала: 2024, Номер 136(47)

Опубликована: Авг. 22, 2024

Abstract The inhibition of intracellular protein‐protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. transcriptional co‐activator protein and oncogene β‐catenin a prime example such challenging target. Despite extensive targeting efforts, available high‐affinity binders comprise only large molecular weight inhibitors. This hampers the further development therapeutically useful compounds. Herein, we report design considerably smaller peptidomimetic scaffold derived from α‐helical β‐catenin‐binding motif Axin. Sequence maturation bicyclization provided stitched peptide with an unprecedented crosslink architecture. binding mode site were confirmed by crystal structure. Further derivatization yielded inhibitor single‐digit micromolar activity cell‐based assay. study sheds light on how to helix mimetics reduced thereby improving their biological activity.

Язык: Английский

Fluorine-Containing Macrocyclic Peptides and Peptidomimetics DOI Creative Commons
Neshat Rozatian, Stefan Roesner

Organic Chemistry Frontiers, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This review covers recent advances in the synthesis and application of fluorine-containing macrocyclic peptides peptidomimetics.

Язык: Английский

Процитировано

0
Recent highlights of the total synthesis of cyclic peptide natural products DOI Creative Commons
Takayuki Doi, Masaya Kumashiro, Kosuke Ohsawa

и другие.

Natural Product Reports, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This review described the total synthesis of naturally occurring cyclic peptides covering 2020 to 2022 paying particular attention construction their unique structures via macrocyclization.

Язык: Английский

Процитировано

0
Increased Throughput of Combined Stability Testing and Metabolite Identification Using a Sample Multiplexing Strategy for the Optimization of Engineered Cyclic Peptide Drugs DOI

Congliang Sun,

Mark T. Cancilla,

Bahanu Habulihaz

и другие.

Journal of the American Society for Mass Spectrometry, Год журнала: 2025, Номер unknown

Опубликована: Май 23, 2025

Engineered cyclic peptides (ECPs) have been in the spotlight as novel drug modalities for challenging therapeutic targets. Oral delivery of engineered benefits from ease administration. However, one main hurdles developing orally effective peptide drugs is their potential metabolic instability due to enzymatic degradation. To that end, vitro experiments with simulated intestinal fluid (SIF) used assess stability gastrointestinal tract. Currently, evaluations and biotransformation assessments are performed separately, which can be time-consuming result complex data analysis. Presented here a sample multiplexing strategy address these challenges by leveraging Thermo Scientific Orbitrap Astral mass spectrometer two complementary analyzers, enabling simultaneous analysis full scan analyzer injection. Furthermore, we demonstrate 10 pooled into injection without compromising quality decrease instrument run time improve throughput assay.

Язык: Английский

Процитировано

0
Isolation, Total Synthesis and the Structure Determination of the Antifungal Macrocyclic Depsipeptide, Tetraselide DOI Creative Commons
H. Nakahara, Goh Sennari,

Haruki Azami

и другие.

Опубликована: Май 31, 2024

Macrocyclic peptides and depsipeptides are the emerging class of a new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from marine-derived filamentous fungus, possesses unique amphiphilic structural feature that represents five consecutive β-hydroxy-amino acid fatty moieties. Because structure elucidation naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation study chiral pool fragment synthesis to identify two undetermined stereochemistry. Convergent total four remaining plausible isomers tetraselide was accomplished via liquid-phase using soluble hydrophobic tag auxiliaries. The key advance involves coupling by serine/threonine ligation reaction head-to-tail macrolactamization carrier-supported precursors enabled systematic elaboration peptides. Ultimately, determined absolute this natural product.

Язык: Английский

Процитировано

2
Structure‐Based Design of Bicyclic Helical Peptides That Target the Oncogene β‐Catenin DOI Creative Commons
Alejandro Yeste‐Vázquez, Felix M. Paulussen, Mathias Wendt

и другие.

Angewandte Chemie, Год журнала: 2024, Номер 136(47)

Опубликована: Авг. 22, 2024

Abstract The inhibition of intracellular protein‐protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. transcriptional co‐activator protein and oncogene β‐catenin a prime example such challenging target. Despite extensive targeting efforts, available high‐affinity binders comprise only large molecular weight inhibitors. This hampers the further development therapeutically useful compounds. Herein, we report design considerably smaller peptidomimetic scaffold derived from α‐helical β‐catenin‐binding motif Axin. Sequence maturation bicyclization provided stitched peptide with an unprecedented crosslink architecture. binding mode site were confirmed by crystal structure. Further derivatization yielded inhibitor single‐digit micromolar activity cell‐based assay. study sheds light on how to helix mimetics reduced thereby improving their biological activity.

Язык: Английский

Процитировано

2