Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797

Published: Jan. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Language: 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, Journal Year: 2025, Volume and Issue: 26(7), P. 3117 - 3117

Published: March 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.

Language: Английский

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Cyclic peptides: a powerful instrument for advancing biomedical nanotechnologies and drug development

Journal of Pharmaceutical and Biomedical Analysis, Journal Year: 2024, Volume and Issue: 252, P. 116488 - 116488

Published: Sept. 27, 2024

Language: Английский

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Peptide Double-Stapling and Arginine N-Glycosylation Triggered the Development of Therapeutic Antimicrobial Peptides Capable of Killing Drug-Resistant Bacteria in Mice

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Antimicrobial peptides SAAP-148 exhibited excellent antimicrobial activities but suffered from inherent disadvantages, including cytotoxicity and poor proteolytic stability. Herein, we developed a novel strategy combining one unique silver-catalyzed solid-phase glycosylation-enabled arginine N-glycosylation all-hydrocarbon peptide double-stapling, five-round libraries were rationally constructed containing over 50 stapled and/or N-glycosylated peptides. SLP-51 consisting of two introduced staples the C-terminal glycosylation superior in vitro against drug-resistant Gram-positive or -negative clinical isolates. also improved stability than parent SLP-0, importantly, significantly weakened hemolysis. Experimental modeling mechanism research indicated that exerted similar stronger killing abilities by destroying integrality bacterial membranes. In both skin wound pneumonia models, showcased potent therapeutic effect treating MRSA Klebsiella pneumoniae infection vivo dramatical improvement inflammatory injury.

Language: Английский

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Peptide classification landscape: An in-depth systematic literature review on peptide types, databases, datasets, predictors architectures and performance

Computers in Biology and Medicine, Journal Year: 2025, Volume and Issue: 188, P. 109821 - 109821

Published: Feb. 22, 2025

Language: Английский

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Deep learning in the discovery of antiviral peptides and peptidomimetics: databases and prediction tools

Molecular Diversity, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Language: Английский

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Computational analysis of antimicrobial peptides targeting key receptors in infection-related cardiovascular diseases: molecular docking and dynamics insights

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 14, 2025

Infection-related cardiovascular diseases (CVDs) pose a significant health challenge, driving the need for novel therapeutic strategies to target key receptors involved in inflammation and infection. Antimicrobial peptides (AMPs) show potential disrupt pathogenic processes offer promising approach CVD treatment. This study investigates binding of selected AMPs with critical implicated CVDs, aiming explore their potential. A comprehensive computational was employed assess AMP interactions CVD-related receptors, including ACE2, CRP, MMP9, NLRP3, TLR4. Molecular docking studies identified high affinities these targets, notably Tachystatin, Pleurocidin, Subtilisin A, which showed strong MMP9. Following docking, 100 ns molecular dynamics (MD) simulations confirmed stability AMP-receptor complexes, MM/PBSA calculations provided quantitative insights into energies, underscoring modulate receptor activity infection contexts. The highlights targeting infection-related pathways CVDs. These demonstrate properties models. Future research should focus on vitro vivo confirm efficacy safety, paving way clinical applications managing conditions.

Language: Английский

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Recent Advances in Augmenting the Therapeutic Efficacy of Peptide–Drug Conjugates

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

There is an urgent need for the development of safe and effective modalities treatment diseases owing to drug resistance, undesired side effects, poor clinical outcomes. Combining cell-targeting efficient cell-killing properties, peptide-drug conjugates (PDCs) have demonstrated superior efficacy compared with peptides payloads alone. However, innovative molecular designs PDCs are essential further improving targeting precision, protease resistance stability, cell permeability, overall efficacy. Several strategies been developed address these challenges, such as multivalency approaches, bispecific targeting, long-acting PDCs. Other novel strategies, including overcoming biological barriers, conjugating functional payloads, macropinocytosis, also shown promise. This perspective compiles most recent enhancing PDC efficacy, highlights key advancements in PDC, provides insights on future directions

Language: Английский

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Therapeutic peptides: chemical strategies fortify peptides for enhanced disease treatment efficacy

Amino Acids, Journal Year: 2025, Volume and Issue: 57(1)

Published: May 8, 2025

Language: Английский

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Developing Stapled Aptamers with a Constrained Conformation for Osteogenesis Imperfect Therapeutics

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 18883 - 18894

Published: Oct. 29, 2024

Despite the extensive development of aptamers in basic research, only a limited number have successfully progressed to clinical trials. This limitation is primarily attributed inherent instability aptamers' conformation, resulting low affinity, poor serum stability, and inconsistent potency, posing significant challenge their stabilization. Herein, we established feasible strategy develop staple using predicted binding conformations titration cross-linking (TTC) method. Through this strategy, synthesized various stapled sclerostin with over 70% yield. Importantly, demonstrated that significantly enhanced affinity (approximately 20-fold) stability (negligible degradation within 32 h). Moreover, an osteogenesis imperfecta mouse model (Col1a2+/G610C mice), aptamer (named c-0127OA) exhibited potent antagonistic effect on sclerostin, leading anabolic bone potential. Collectively, our stapling effective stabilizing c-0127OA emerging as promising therapeutic candidate for imperfecta.

Language: Английский

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