Late-Stage Peptide Modification and Macrocyclization Enabled by Tertiary Amine Catalyzed Tryptophan Allylation

Chemical Science, Journal Year: 2024, Volume and Issue: 15(28), P. 11099 - 11107

Published: Jan. 1, 2024

An unprecedented tertiary amine catalyzed peptide allylation between Trp and MBH carbonates was disclosed, to enable late-stage functionalization macrocyclization both in traditional homogeneous phase on-resins SPPS.

Language: Английский

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Isolation, Virtual Screening, and Evaluation of Hazelnut-Derived Immunoactive Peptides for the Inhibition of SARS-CoV-2 Main Protease

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(20), P. 11561 - 11576

Published: May 13, 2024

The aim of this study is to validate the activity hazelnut (Corylus avellana L.)-derived immunoactive peptides inhibiting main protease (Mpro) SARS-CoV-2 and further unveil their interaction mechanism using in vitro assays, molecular dynamics (MD) simulations, binding free energy calculations. In general, enzymatic hydrolysis components, especially weight < 3 kDa, possess good immune as measured by proliferation ability mouse splenic lymphocytes phagocytic peritoneal macrophages. Over 866 unique peptide sequences were isolated, purified, then identified nanohigh-performance liquid chromatography/tandem mass spectrometry (NANO-HPLC-MS/MS) from protein hydrolysates, but Trp-Trp-Asn-Leu-Asn (WWNLN) Trp-Ala-Val-Leu-Lys (WAVLK) particular are found increase cell viability capacity RAW264.7 macrophages well promote secretion cytokines nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β). Fluorescence resonance transfer assay elucidated that WWNLN WAVLK exhibit excellent inhibitory potency against Mpro, with IC50 values 6.695 16.750 μM, respectively. Classical all-atom MD simulations show hydrogen bonds play a pivotal role stabilizing complex conformation protein–peptide interaction. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation indicates has lower Mpro than WAVLK. Furthermore, adsorption, distribution, metabolism, excretion, toxicity (ADMET) predictions illustrate favorable drug-likeness pharmacokinetic properties compared This provides new understanding immunomodulatory hydrolysates sheds light on inhibitors targeting Mpro.

Language: Английский

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Macrocyclization of Maleimide-Decorated Peptides via Late-Stage Rh(III)-Catalyzed Trp(C7) Alkenylation

Organic Letters, Journal Year: 2023, Volume and Issue: 25(14), P. 2456 - 2460

Published: March 31, 2023

Here, we report a novel strategy for constructing maleimide-containing peptides and cyclic using Rh(III)-catalyzed tryptophan (Trp) (C7) alkenylation, which is challenging due to the inherent reactivity of indole benzenoid ring. This method scalable exhibits broad substrate scope. The utility this protocol could further be demonstrated by synthesis peptide conjugates with natural products amino acids as well construction maleimide-braced peptides.

Language: Английский

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Late-Stage Stitching Enabled by Palladium-Catalyzed Tryptophan C4 Amination: Peptide Ligation and Cyclodimerization

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Here, we report on methods for late-stage peptide diversification through palladium-catalyzed site-selective C(sp2)–H amination of tryptophan residues at the C4 position, utilizing tryptophan-amine cross-links. Our strategy enables practical access to C–N bonds, facilitating construction cyclopeptides via cyclodimerization structurally complex peptides, which poses significant challenges organic synthesis. The synthetic utility this protocol is demonstrated synthesis 30- 38-membered macrocyclic peptides.

Language: Английский

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Revisiting the potential of natural antimicrobial peptides against emerging respiratory viral disease: a review

3 Biotech, Journal Year: 2025, Volume and Issue: 15(2)

Published: Jan. 13, 2025

Language: Английский

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Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH

Life Metabolism, Journal Year: 2025, Volume and Issue: 4(2)

Published: Feb. 7, 2025

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of dysfunction-associated steatohepatitis (MASH). All reported FXR target ligand-binding pocket (LBP) receptor, whereas antagonist acting on non-LBP site nuclear (NR) is conceived as a promising strategy discover novel antagonist. Here, we postulated hypothesis antagonizing by disrupting interaction between and coactivators, successfully developed series macrocyclic peptides based this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity FXR, but also demonstrates high degree selectivity towards other NRs. Moreover, has potential therapeutic benefit MASH an intestinal FXR-dependent manner, along with commendable safety profile. Mechanistically, distinct from known antagonists, specifically binds coactivator binding which can block recruitment, reducing circulation intestine-derived ceramides liver, promoting release glucagon-like peptide-1 (GLP-1). Overall, identify that targets FXR-coactivator interaction, paving way new approach treating antagonists.

Language: Английский

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A water-soluble cationic [2]biphenyl-extended pillar[6]arene: synthesis, host-guest interaction with hemin and application in chemodynamic/photodynamic cancer therapy

Chemical Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A water-soluble cationic [2]biphenyl-extended pillar[6]arene (CBpExP 6 ) was synthesized, forming a stable 1 : complex with hemin to enhance its stability for cancer CDT/PDT applications.

Language: Английский

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Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(5), P. 617 - 617

Published: April 24, 2025

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein However, despite potential, the synthesis optimization of macrocyclic compounds present considerable challenges related structural complexity, synthetic accessibility, attainment favorable drug-like properties, particularly cell permeability oral bioavailability. Recent advancements methodologies expanded chemical space accessible macrocycles, enabling creation diverse pharmacologically active compounds. Concurrent developments computational strategies further enhanced macrocycle design, providing valuable insights into predicting molecular properties essential for efficacy. Additionally, a deeper understanding macrocycles’ conformational adaptability, especially ability internally shield polar functionalities improve membrane permeability, has significantly informed rational design. This review discusses recent innovations that advanced over past five years. It emphasizes importance integrating these overcome existing challenges, illustrating how synergy expands potential diversity macrocycles. Selected case studies underscore practical impact integrated approaches, highlighting promising applications across biomedical targets.

Language: Английский

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Rh(III)-catalyzed late-stage C-H alkenylation and macrolactamization for the synthesis of cyclic peptides with unique Trp(C7)-alkene crosslinks

Chinese Chemical Letters, Journal Year: 2023, Volume and Issue: 35(8), P. 109408 - 109408

Published: Dec. 19, 2023

Language: Английский

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Recent Progress on Transition Metal Catalyzed Macrocyclizations Based on C‐H Bond Activation at Heterocyclic Scaffolds

Chemistry - An Asian Journal, Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

Abstract Macrocycles are essential in protein‐protein interactions and the preferential intake of bioactive scaffolds. commonly synthesized by late‐stage macrolactonizations, macrolactamizations, transition metal‐catalyzed ring‐closing metathesis, S−S bond‐forming reactions, copper‐catalyzed alkyne–azide cycloaddition. Recently, C−H activation strategies have gained significant interest among chemists to synthesize macrocycles. This article provides a comprehensive overview macrocyclization via bond functionalization heterocycle‐containing peptides, annulations, heterocycle‐ring construction through direct functionalization. In first part, palladium salt catalyzed coupling with indolyl C(sp 3 )−H 2 bonds for is reported. The second part summarizes rhodium‐catalyzed macrocyclizations site‐selective Earth‐abundant, less toxic 3d metal Mn‐catalyzed cyclizations reported latter part. summary expected spark emerging methods macrocycle production organic synthesis chemical biology practitioners, helping develop discipline. We hope that this mini‐review will also inspire synthetic explore new broadly applicable C−C intramolecular activation.

Language: Английский

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