Protein Silencing with Self-Peptides

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Designing functional molecules which can recognize and modify the activity of a specific protein is frequently encountered challenge in biology pharmaceutical chemistry, requires major effort for each target. Here we demonstrate that "self-peptides", parts folded proteins by their nature are recognizable rest protein, provide general route to developing such molecules. Such synthetic peptide with chemically prestabilized conformation incorporate into target during its folding, potentially displace native counterpart cause deficits. This strategy especially promising β-barrel topology, as seam barrel provides vulnerable We this using green fluorescent (EGFP) model, fluorescence direct reporter function. Refolding EGFP presence 35 μM disulfide-stabilized 20-residue self-peptide (SP1, resembles seam, strands 3 11, GFP) quenches 97%. A same composition but different sequence only 40% effective, demonstrating silencing relatively specific. Fluorescence correlation spectroscopy time-resolved lifetime measurements show SP1 causes complete long-term it incorporates into. result principle have biological application if synthesis, before nascent folds. indeed silence sfGFP (closely related EGFP) ribosomal synthesis an vitro translation system. Therefore, self-peptides present protein-specific silencers physiological applications.

Language: Английский

A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson’s Disease

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(27), P. 6439 - 6448

Published: June 28, 2024

In recent work we proposed that interdiction in the earliest contact-formation events along folding pathway of key viral proteins could provide a novel avenue for therapeutic drug design. this Perspective explore potential applicability protein strategy realm neurodegenerative diseases with specific focus on synucleinopathies. order to fulfill goal review proposal and its practical challenges, present new results concerning design strategies possible peptide drugs be useful preventing α-synuclein aggregation.

Language: Английский

Computational Assessment of Clinical Drugs against SARS‐CoV‐2: Foreseeing Molecular Mechanisms and Potent Mpro Inhibitors

ChemPhysChem, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 29, 2024

Abstract The emergence of new SARS‐CoV‐2 variants concern (VOC) is a propulsion for accelerated potential therapeutic discovery. SARS‐CoV‐2’s main protease (Mpro), essential host cell viral replication, pre‐eminent druggable protein target. Here, we perform extensive drug re‐profiling the comprehensive Excelra database, which compiles various under‐trial candidates COVID‐19 treatment. For mechanistic understanding, most promising screened‐out molecules with targets are subjected to molecular dynamics (MD) simulations. Post‐MD analyses demonstrate Darunavir, Ponatinib, and Tomivosertib forming stable complex Mpro, characterized by less fluctuation Cα atoms, smooth root‐mean‐square deviation (RMSD), robust contact active site residues. Likewise, they all have lower binding free energy demonstrating strong affinity. In landscape profiles, distances from His41 Cys145 exhibit single minima basin, implying their preponderance in proximity Mpro's catalytic dyad. Overall, computational assessment earmarks emphasizing on carrying out exhaustive biochemical experiments along clinical trials. work lays foundation interventions treating COVID‐19.

Language: Английский