Characterization and Fluctuations of an Ivermectin Binding Site at the Lipid Raft Interface of the N-Terminal Domain (NTD) of the Spike Protein of SARS-CoV-2 Variants DOI Creative Commons

Marine Lefebvre,

Henri Chahinian, Bernard La Scola

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(12), P. 1836 - 1836

Published: Nov. 27, 2024

Most studies on the docking of ivermectin spike protein SARS-CoV-2 concern receptor binding domain (RBD) and, more precisely, RBD interface recognized by ACE2 receptor. The N-terminal (NTD), which controls initial attachment virus to lipid raft gangliosides, has not received attention it deserves. In this study, we combined molecular modeling and physicochemical approaches analyze mode interaction with NTD-facing rafts host cell membrane. We characterize a area that presents point mutations deletions in successive variants from strain omicron KP.3 circulating many countries 2024. show exceptional flexibility, allowing drug bind all tested. energy is specific each variant, classification according their affinity for following ascending order: Omicron < Delta BA.5 Alpha Wuhan (B.1) BA.1. site subject important variations NTD, including Y144 deletion. It overlaps ganglioside as demonstrated studies. These results suggest new mechanism antiviral action based competitive inhibition rafts. current variant still ivermectin, although an slightly lower than strain.

Language: Английский

Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow DOI Creative Commons
Jacques Fantini, Fodil Azzaz, Coralie Di Scala

et al.

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

Citations

2
Cholesterol-Dependent Serotonin Insertion Controlled by Gangliosides in Model Lipid Membranes DOI Open Access
Jacques Fantini, Fodil Azzaz,

Ryad Bennaï

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10194 - 10194

Published: Sept. 23, 2024

Serotonin is distinct among synaptic neurotransmitters because it amphipathic and released from vesicles at concentrations superior to its water solubility limit (270 mM in for a of 110 mM). Hence, serotonin mostly aggregated the cleft, due extensive aromatic stacking. This important characteristic has received scant attention, as most representations serotonergic synapse take warranted that molecules are present monomers after vesicle exocytosis. Using combination silico physicochemical approaches new experimental device mimicking conditions, we show aggregates efficiently dissolved by gangliosides (especially GM1) postsynaptic membranes. initial interaction, driven electrostatic forces, attracts insoluble resolves micelles into monomers. also interacts with cholesterol via set CH-π van der Waals interactions. Thus, act together functional serotonin-collecting funnel on brain cell Based this unique mode interaction membranes, propose model transmission takes account post-exocytosis solubilizing effect aggregates.

Language: Английский

Citations

1
Characterization and Fluctuations of an Ivermectin Binding Site at the Lipid Raft Interface of the N-Terminal Domain (NTD) of the Spike Protein of SARS-CoV-2 Variants DOI Creative Commons

Marine Lefebvre,

Henri Chahinian, Bernard La Scola

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(12), P. 1836 - 1836

Published: Nov. 27, 2024

Most studies on the docking of ivermectin spike protein SARS-CoV-2 concern receptor binding domain (RBD) and, more precisely, RBD interface recognized by ACE2 receptor. The N-terminal (NTD), which controls initial attachment virus to lipid raft gangliosides, has not received attention it deserves. In this study, we combined molecular modeling and physicochemical approaches analyze mode interaction with NTD-facing rafts host cell membrane. We characterize a area that presents point mutations deletions in successive variants from strain omicron KP.3 circulating many countries 2024. show exceptional flexibility, allowing drug bind all tested. energy is specific each variant, classification according their affinity for following ascending order: Omicron < Delta BA.5 Alpha Wuhan (B.1) BA.1. site subject important variations NTD, including Y144 deletion. It overlaps ganglioside as demonstrated studies. These results suggest new mechanism antiviral action based competitive inhibition rafts. current variant still ivermectin, although an slightly lower than strain.

Language: Английский

Citations

0