Tetrodotoxin (TTX), a potent Site-1 sodium channel blocker (S1SCB), offers highly effective local anesthetic properties with minimal addiction potential. To fully leverage TTX's capabilities as a local anesthetic, it is crucial to develop a drug delivery system that balances its systemic toxicity with its therapeutic efficacy. Recent studies have shown that peptide mixtures, derived from fragments of Site-1 sodium channel proteins and enhanced with hydrophobic tails (designated MP1 and MP2), can self-assemble into nanostructures that exhibit remarkable sustained-release capabilities for TTX. Despite the profound impact that the addition of a hydrophobic tail has on altering the release behavior of the original peptides, the atomic-level interactions and mechanisms underlying this phenomenon remain poorly understood. In this study, a combination of ColabFold and molecular dynamics (MD) simulations were used to investigate the binding interactions between TTX and the nanostructures formed by MP1 and MP2 at an atomic level. Our findings agree with experimental observations and indicate that the MP1/MP2 nanostructure demonstrates greater stability and higher binding affinity for TTX compared to their non-modified counterparts, P1 and P2. The analysis of the simulations revealed that charged amino acids, specifically aspartic acid (ASP) and glutamic acid (GLU), on the peptides are crucial for strong TTX binding and serve as the primary functional sites. Additionally, the stability of the nanostructure significantly affects TTX binding affinity, elucidating why P1, P2, MP1, and MP2 exhibit different binding capabilities despite containing identical charged residues. The results reported here may provide fundamental information to drive future research and enhance the development of TTX-based drug delivery systems.
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http://dx.doi.org/10.3390/molecules30010061 | DOI Listing |
Molecules
December 2024
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USA.
Tetrodotoxin (TTX), a potent Site-1 sodium channel blocker (S1SCB), offers highly effective local anesthetic properties with minimal addiction potential. To fully leverage TTX's capabilities as a local anesthetic, it is crucial to develop a drug delivery system that balances its systemic toxicity with its therapeutic efficacy. Recent studies have shown that peptide mixtures, derived from fragments of Site-1 sodium channel proteins and enhanced with hydrophobic tails (designated MP1 and MP2), can self-assemble into nanostructures that exhibit remarkable sustained-release capabilities for TTX.
View Article and Find Full Text PDFBraz Dent J
December 2024
Department of Dentistry, Pontifical Catholic University of Minas Gerais, Belo Horizonte, MG, Brazil.
Unlabelled: The amount of residual dentin thickness and tooth position in the dental arch is crucial to determine whether an intraradicular post should be used. This study aimed to compare stress distribution on the root dentin of an endodontically treated tooth rehabilitated with CAD/CAM milled glass fiber posts (MP), cast metal posts (CMP), or prefabricated posts (PP) with or without ferrule support, using the finite element method.
Materials And Methods: A human upper central incisor was selected, scanned, and treated endodontically.
Transl Vis Sci Technol
December 2024
Center for Visual Science, University of Rochester, Rochester, NY, USA.
Purpose: We evaluated through-focus visual performance and accommodative response in young subjects through three segmented multifocal designs for myopia control, mapped on the spatial light modulator of a monocular adaptive optics visual simulator (AOVS), and compared with single vision (SV).
Methods: The segmented multifocal patterns included a 4 mm diameter center distance zone and offset peripheral defocus (MP1), astigmatism and coma (MP2), or a combination (MP3). High-contrast logMAR visual acuity (VA) was measured with monochromatic stimuli (555 nm).
Heredity (Edinb)
January 2025
Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus C, Denmark.
Genome-wide association study (GWAS) is a powerful tool for identifying marker-trait associations that can accelerate breeding progress. Yet, its power is typically constrained in newly established breeding programs where large phenotypic and genotypic datasets have not yet accumulated. Expanding the dataset by inclusion of data from well-established breeding programs with many years of phenotyping and genotyping can potentially address this problem.
View Article and Find Full Text PDFJ Obstet Gynaecol Res
January 2025
Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan, Turkey.
Aim: Research on the effects of methylphenidate on female fertility is limited. This study evaluated the effects of methylphenidate on reproductive function, oxidants, antioxidants, proinflammatory cytokines, prolactin, and cortisol in female rats.
Methods: Forty-eight albino Wistar female rats were divided into four groups consisting of 12 rats, which were given pure water orally once daily for 7 days (HG-1), 10 mg/kg methylphenidate orally once daily for 7 days (MP-1), pure water orally once daily for 30 days (HG-2), and 10 mg/kg methylphenidate orally once daily for 30 days (MP-2).
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