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Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers

Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-...

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Detalles Bibliográficos
Autores principales: Mocanu, Cosmin Stefan, Niculaua, Marius, Zbancioc, Gheorghita, Mangalagiu, Violeta, Drochioiu, Gabi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911100/
https://www.ncbi.nlm.nih.gov/pubmed/35269999
http://dx.doi.org/10.3390/ijms23052857
Descripción
Sumario:Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer’s disease (AD). We started with five peptides ((15)QKLVFF(20), (16)KLVFF(20), (17)LVFF(20), (16)KLVF(19) and (15)QKLV(18)), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides (17)LVFF(20), NA-(17)LVFF(20), (16)KLVF(19) and NA-(16)KLVF(19) (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-(16)KLVF(19) possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of (16)KLVF(19). Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-(16)KLVF(19) may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.