ORCID Profile
0000-0001-6945-7357
Current Organisations
National Neuroscience Institute
,
Commissariat à l’énergie atomique et aux énergies alternatives
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Publications
Discovery and Structure–Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening
Publisher: American Chemical Society (ACS)
Date: 26-07-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00356
Abstract: Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.
Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S41467-021-23799-1
Abstract: Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.
Rivastigmine and metabolite analogues with putative Alzheimer’s disease-modifying properties in a Caenorhabditis elegans model
Publisher: Springer Science and Business Media LLC
Date: 22-03-2019
DOI: 10.1038/S42004-019-0133-4
Abstract: The development of polyphenols as drugs for Alzheimer’s disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Aβ) fibrillation, protect against Aβ 42 -induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Aβ 42 , with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.
Related Organisations
Commissariat À L’énergie Atomique Et Aux Énergies Alternatives
Location: France
Related Funding Activities
No related grants have been discovered for Eugenio de la Mora.