From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Caterina Pont; Tiziana Ginex; Christian Griñán-Ferré; Matthias Scheiner; Alexia Mattellone; Noemí Martínez; Elsa M Arce; Yolanda Soriano-Fernández; Marina Naldi; Angela De Simone; Marta Barenys; Jesús Gómez-Catalán; Belén Pérez; Raimon Sabate; Vincenza Andrisano; María Isabel Loza; José Brea; Manuela Bartolini; Maria Laura Bolognesi; Michael Decker; Mercè Pallàs; F Javier Luque; Diego Muñoz-Torrero

doi:10.1016/j.ejmech.2021.113779

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Eur J Med Chem. 2021 Dec 5:225:113779. doi: 10.1016/j.ejmech.2021.113779. Epub 2021 Aug 16.

Authors

Caterina Pont¹, Tiziana Ginex², Christian Griñán-Ferré³, Matthias Scheiner⁴, Alexia Mattellone⁵, Noemí Martínez¹, Elsa M Arce¹, Yolanda Soriano-Fernández³, Marina Naldi⁵, Angela De Simone⁶, Marta Barenys⁷, Jesús Gómez-Catalán⁷, Belén Pérez⁸, Raimon Sabate⁹, Vincenza Andrisano¹⁰, María Isabel Loza¹¹, José Brea¹¹, Manuela Bartolini⁵, Maria Laura Bolognesi⁵, Michael Decker⁴, Mercè Pallàs³, F Javier Luque¹², Diego Muñoz-Torrero¹³

Affiliations

¹ Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
² Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, IBUB, and Institute of Theoretical and Computational Chemistry (IQTC), UB, E-08921, Santa Coloma de Gramenet, Spain.
³ Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Neuroscience, University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
⁴ Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, DE-97074, Würzburg, Germany.
⁵ Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy.
⁶ Department of Drug Science and Technology, University of Turin, I-10125, Torino, Italy.
⁷ GRET, INSA-UB, and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
⁸ Department of Pharmacology, Therapeutics, and Toxicology, Autonomous University of Barcelona, E-08193, Bellaterra, Spain.
⁹ Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
¹⁰ Department for Life Quality Studies, Alma Mater Studiorum University of Bologna, Corso d'Augusto 237, I-47921, Rimini, Italy.
¹¹ BioFarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Av. de Barcelona s/n, E-15782, Santiago de Compostela, Spain.
¹² Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, IBUB, and Institute of Theoretical and Computational Chemistry (IQTC), UB, E-08921, Santa Coloma de Gramenet, Spain. Electronic address: fjluque@ub.edu.
¹³ Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.

PMID: 34418785
DOI: 10.1016/j.ejmech.2021.113779

Abstract

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

Keywords: Alzheimer's disease; Cryptic pocket; Multitarget compound; SAMP8; Zebrafish embryo.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Aminoquinolines / chemical synthesis
Aminoquinolines / chemistry
Aminoquinolines / pharmacology*
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Brain / metabolism
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Molecular Dynamics Simulation
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacology*
Recombinant Proteins / metabolism
Structure-Activity Relationship
tau Proteins / antagonists & inhibitors
tau Proteins / metabolism

Substances

Aminoquinolines
Amyloid beta-Peptides
Heterocyclic Compounds, 4 or More Rings
Neuroprotective Agents
Recombinant Proteins
huprine Y
tau Proteins
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human