Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N-Acyl-N-alkyl Sulfonamide Warhead

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(12), С. 4766 - 4774

Опубликована: Март 18, 2021

Protein–protein interactions (PPIs) intimately govern various biological processes and disease states therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible human double minute 2 (HDM2)/p53 PPI, which employ a reactive N-acyl-N-alkyl sulfonamide (NASA) group warhead. Mass-based analysis successfully revealed kinetics covalent inhibition modification sites on HDM2 N-terminal α-amine Tyr67, both rarely seen in traditional inhibitors. Finally, demonstrated prolonged p53-pathway activation more effective induction p53-mediated cell death comparison noncovalent inhibitor. This study highlights potential NASA warhead versatile electrophile opens new avenues rational design PPI

Язык: Английский

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Computational design of novel protein–protein interactions – An overview on methodological approaches and applications

Current Opinion in Structural Biology, Год журнала: 2022, Номер 74, С. 102370 - 102370

Опубликована: Апрель 8, 2022

Protein-protein interactions (PPIs) govern numerous cellular functions in terms of signaling, transport, defense and many others. Designing novel PPIs poses a fundamental challenge to our understanding molecular interactions. The capability robustly engineer has immense potential for the development synthetic biology tools protein-based therapeutics. Over last decades, efforts this area have relied purely on experimental approaches, but more recently, computational protein design made important contributions. Template-based approaches utilize known transplant critical residues onto heterologous scaffolds. De novo instead uses methods generate binding motifs, allowing broader scope sites engaged targets. Here, we review successful cases, giving an overview methodological used templated de PPI design.

Язык: Английский

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De novo molecular design with deep molecular generative models for PPI inhibitors

Briefings in Bioinformatics, Год журнала: 2022, Номер 23(4)

Опубликована: Июль 13, 2022

We construct a protein-protein interaction (PPI) targeted drug-likeness dataset and propose deep molecular generative framework to generate novel molecules from the features of seed compounds. This gains inspiration published models, uses key associated with PPI inhibitors as input develops models for de novo design inhibitors. For first time, quantitative estimation index compounds targeting was applied evaluation generation model PPI-targeted Our results estimated that generated had better drug-likeness. Additionally, our also exhibits comparable performance other several state-of-the-art molecule models. The share chemical space iPPI-DB demonstrated by analysis. peptide characterization-oriented ligand-based are explored. Finally, we recommend this will be an important step forward therapeutics.

Язык: Английский

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Single-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Апрель 4, 2023

In drug discovery, efficient screening of protein-drug interactions (PDIs) is hampered by the limitations current biophysical approaches. Here, we develop a biological nanopore sensor for single-molecule detection proteins and PDIs using pore-forming toxin YaxAB. Using this YaxAB nanopore, demonstrate label-free, between anticancer Bcl-xL protein small-molecule drugs as well Bak-BH3 peptide. The long funnel-shaped structure nanofluidic characteristics enable electro-osmotic trapping diverse folded high-resolution monitoring PDIs. Distinctive event distributions observed in two-dimensional (ΔI/Io-versus-IN) plot illustrate ability to discriminate individual bound from non-binders. Taken together, our results present robust platform ultrasensitive, PDIs, opening up possibility low-cost, highly discovery against targets.

Язык: Английский

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Fragment-based drug discovery supports drugging ‘undruggable’ protein–protein interactions

Trends in Biochemical Sciences, Год журнала: 2023, Номер 48(6), С. 539 - 552

Опубликована: Фев. 24, 2023

Язык: Английский

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Three- and four-stranded nucleic acid structures and their ligands

RSC Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Nucleic acids have the potential to form not only duplexes, but also various non-canonical secondary structures in living cells. Structure- and sequence-selective binding of small molecules is required for their cellular applications.

Язык: Английский

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Structure-based discovery of hydrocarbon-stapled paxillin peptides that block FAK scaffolding in cancer

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 28, 2025

Abstract The focal adhesion kinase (FAK) scaffold provides FAK-targeted cancer therapeutics with greater efficacy and specificity than traditional inhibitors. FAK function largely involves the interaction between FAK’s targeting (FAT) domain paxillin, ultimately regulating many hallmarks of cancer. We report design paxillin LD-motif mimetics that successfully inhibit FAT-paxillin interaction. Chemical biochemical screening identifies stapled peptide 1907, a high affinity binder FAT four-helix bundle ~100-fold binding native LD2-sequence. X-ray co-crystal structure FAT-1907 complex is solved. Myristoylated 1907-analog, 2012, delocalizes from adhesions, induces cell apoptosis, reduces in vitro viability invasion, decreases tumor burden B16F10 melanoma female mice. Enzymatic inhibition produces no comparable effects. Herein, we describe biologically potent therapeutic strategy to target FAK-paxillin complex, previously deemed undruggable protein-protein

Язык: Английский

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The Potential of Peptide-Based Inhibitors in Disrupting Protein–Protein Interactions for Targeted Cancer Therapy

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3117 - 3117

Опубликована: Март 28, 2025

Protein-protein interactions (PPIs) form an intricate cellular network known as the interactome, which is essential for various processes, such gene regulation, signal transduction, and metabolic pathways. The dysregulation of this has been closely linked to disease states. In cancer, these aberrant PPIs, termed oncogenic PPIs (OncoPPIs), are involved in tumour formation proliferation. Therefore, inhibition OncoPPIs becomes a strategy targeted cancer therapy. Small molecule inhibitors have dominant PPI owing their small size ability cross cell membranes. However, peptide-based emerged compelling alternatives, offering distinct advantages over inhibitors. Peptides, with larger flexible backbones, can effectively engage broad interfaces PPIs. Their high specificity, lower toxicity, ease modification make them promising candidates Over past decade, significant advancements made developing This review discusses critical aspects targeting emphasizes significance therapy, explores using therapeutic agents. It also highlights recent progress peptide design aimed at overcoming limitations therapeutics, comprehensive overview current landscape potential treatment.

Язык: Английский

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Immobilization of l-asparaginase on gold nanoparticles for novel drug delivery approach as anti-cancer agent against human breast carcinoma cells

Journal of Materials Research and Technology, Год журнала: 2020, Номер 9(6), С. 15394 - 15411

Опубликована: Окт. 23, 2020

l-asparaginase is an amidohydrolase enzyme that widely identified as one of the most potential anti cancerous drugs. Nevertheless, this drug poorly bioavailable and hence its pharmaceutical uses are limited. To improve bioactivity, was loaded on gold nanoparticles (GNPs) along with Arg-Gly-Asp (RGD) peptide direct to targeted cancer cells aim enhancing anticancer efficiency. Successful preparation GNPs conjugate (GNPs-PEG-l-asparaginase-RGD) verified delineated by employing UV–VIS spectrophotometer, FTIR, XRD, FE-SEM, TEM. Fourier Transform Infrared (FT-IR), X-Ray Diffraction (XRD), Field Emission Scanning Electron Microscopic (FE-SEM), Transmission Microscopy (TEM). The efficiency target distribute in MCF-7 evaluated using high fluorescent signals confirmed fluorescence microscopy. A variety parameters were tested investigate each compound toward vitro. demonstrated significant antioxidant effects tumor targeting efficacy distribution cells. It caused a decrease cell proliferation rate clonogenicity cells, while initiating apoptosis promoting cycle arrest at G2/M, flow cytometry analysis. These coupled upregulating pro-apoptotic p53 downregulating anti-apoptotic Bcl-2, which resulted alleviation mitochondrial membrane (MMP) and, thereby, secretion cytochrome c. outcomes present study propose feasibility for further development novel agent against

Язык: Английский

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<p>Current Challenges and Opportunities in Designing Protein–Protein Interaction Targeted Drugs</p>

Advances and Applications in Bioinformatics and Chemistry, Год журнала: 2020, Номер Volume 13, С. 11 - 25

Опубликована: Ноя. 1, 2020

Abstract: It has been noticed that the efficiency of drug development decreasing in past few decades. To overcome situation, protein–protein interactions (PPIs) have identified as new targets early 2000. PPIs are more abundant human cells than single proteins and play numerous important roles cellular processes including diseases. However, very different physicochemical features from conventional targets, which make targeting challenging. Therefore, now, only a small number PPI inhibitors approved or progressed to stage clinical trial. In this article, we first overview previous works analyzed differences between with ligands drugs their binding pockets. Then, constructed an up-to-date list currently under trial bound drug–target structures available. Using dataset, using several scores druggability. Druggability showed sites less druggable pockets drugs, also indicates do not follow rules for design, such Lipinski’s rule five. Our analyses suggest developing would be beneficial guiding PPI-drug discovery. Keywords: interaction, PPI, discovery

Язык: Английский

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