Publications by authors named "Danilo Milardi"

72 Publications

Tau/Aβ chimera peptides: A Thioflavin-T and MALDI-TOF study of Aβ amyloidosis in the presence of Cu(II) or Zn(II) ions and total lipid brain extract (TLBE) vesicles.

Chem Phys Lipids 2021 Jul 22;237:105085. Epub 2021 Apr 22.

Istituto di Cristallografia S.S. di Catania, Via P. Gaifami 18, 95126, Catania, Italy. Electronic address:

Currently, Alzheimer's Disease (AD) is a complex neurodegenerative condition, with limited therapeutic options. Several factors, like Amyloid β (Aβ) aggregation, tau protein hyperphosphorylation, bio-metals dyshomeostasis and oxidative stress contribute to AD pathogenesis. These pathogenic processes might occur in the aqueous phase but also on neuronal membranes. Thus, investigating the connection between Aβ and biomembranes, becomes important for unveiling the molecular mechanism underlying Aβ amyloidosis as a critical event in AD pathology. In this work, the interaction of two peptides, made up with hybrid sequences from Tau protein 9-16 (EVMEDHAG) or 26-33 (QGGYTMHQ) N-terminal domain and Aβ (KLVFF) hydrophobic region, with full length Aβ40 or Aβ42 peptides is reported. The studied "chimera" peptides Ac-EVMEDHAGKLVFF-NH (τ-KL) and Ac-QGGYTMHQKLVFF-NH (τ-KL) are endowed with Aβ recognition and metal ion interaction capabilities provided by the tau or Aβ sequences, respectively. These peptides were characterized in previous study along with their metal dependent interaction and amyloidogenesis, either in the presence or absence of metal ion and artificial membranes made up with Total Lipid Brain Extract (TLBE) components, (Sciacca et al., 2020). In the present paper, the ability of the two peptides to inhibit Aβ aggregation is studied using composite experimental conditions including aqueous solution, the presence of metal ions (Cu or Zn), the presence of lipid vesicles mimicking neuronal membranes as well as the co-presence of metals and TLBE artificial membranes. We used Thioflavine-T (ThT) fluorescence or MALDI-TOF spectrometry analysis of Aβ limited proteolysis to respectively monitor the Aβ aggregation kinetic or validation of the Aβ interacting regions. We demonstrate that τ-KL and τ-KL peptides differently affect Aβ aggregation kinetics, with the tau sequence playing a crucial role. The results are discussed in terms of chimera's peptides hydrophobicity and electrostatic driven interactions at the aqueous/membrane interface.
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http://dx.doi.org/10.1016/j.chemphyslip.2021.105085DOI Listing
July 2021

The interplay between lipid and Aβ amyloid homeostasis in Alzheimer's Disease: risk factors and therapeutic opportunities.

Chem Phys Lipids 2021 May 4;236:105072. Epub 2021 Mar 4.

Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania, Italy. Electronic address:

Alzheimer's Diseases (AD) is characterized by the accumulation of amyloid deposits of Aβ peptide in the brain. Besides genetic background, the presence of other diseases and an unhealthy lifestyle are known risk factors for AD development. Albeit accumulating clinical evidence suggests that an impaired lipid metabolism is related to Aβ deposition, mechanistic insights on the link between amyloid fibril formation/clearance and aberrant lipid interactions are still unavailable. Recently, many studies have described the key role played by membrane bound Aβ assemblies in neurotoxicity. Moreover, it has been suggested that a derangement of the ubiquitin proteasome pathway and autophagy is significantly correlated with toxic Aβ aggregation and dysregulation of lipid levels. Thus, studies focusing on the role played by lipids in Aβ aggregation and proteostasis could represent a promising area of investigation for the design of valuable treatments. In this review we examine current knowledge concerning the effects of lipids in Aβ aggregation and degradation processes, focusing on the therapeutic opportunities that a comprehensive understanding of all biophysical, biochemical, and biological processes involved may disclose.
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http://dx.doi.org/10.1016/j.chemphyslip.2021.105072DOI Listing
May 2021

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes.

Chem Rev 2021 02 11;121(3):1845-1893. Epub 2021 Jan 11.

Biophysics, Department of Chemistry, Biomedical Engineering, Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 41809-1055, United States.

The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
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http://dx.doi.org/10.1021/acs.chemrev.0c00981DOI Listing
February 2021

Synthesis of New Tyrosol-Based Phosphodiester Derivatives: Effect on Amyloid β Aggregation and Metal Chelation Ability.

ChemMedChem 2021 Apr 26;16(7):1172-1183. Epub 2021 Jan 26.

Department of Chemical Sciences, University of Napoli Federico II, Via Cintia 4, 80126, Napoli, Italy.

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. Increasing evidence has shown that aggregation of amyloid β (Aβ) and oxidative stress are strictly interconnected, and their modulation might have a positive and synergic effect in contrasting AD-related impairments. Herein, a new and efficient fragment-based approach towards tyrosol phosphodiester derivatives (TPDs) has been developed starting from suitable tyrosol building blocks and exploiting the well-established phosphoramidite chemistry. The antioxidant activity of new TPDs has been tested as well as their ability to inhibit Aβ protein aggregation. In addition, their metal chelating ability has been evaluated as a possible strategy to develop new natural-based entities for the prevention or therapy of AD. Interestingly, TPDs containing a catechol moiety have demonstrated highly promising activity in inhibiting the aggregation of Aβ and a strong ability to chelate biometals such as Cu and Zn .
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http://dx.doi.org/10.1002/cmdc.202000807DOI Listing
April 2021

The change of conditions does not affect Ros87 downhill folding mechanism.

Sci Rep 2020 12 3;10(1):21067. Epub 2020 Dec 3.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Via Vivaldi 43, 81100, Caserta, Italy.

Downhill folding has been defined as a unique thermodynamic process involving a conformations ensemble that progressively loses structure with the decrease of protein stability. Downhill folders are estimated to be rather rare in nature as they miss an energetically substantial folding barrier that can protect against aggregation and proteolysis. We have previously demonstrated that the prokaryotic zinc finger protein Ros87 shows a bipartite folding/unfolding process in which a metal binding intermediate converts to the native structure through a delicate barrier-less downhill transition. Significant variation in folding scenarios can be detected within protein families with high sequence identity and very similar folds and for the same sequence by varying conditions. For this reason, we here show, by means of DSC, CD and NMR, that also in different pH and ionic strength conditions Ros87 retains its partly downhill folding scenario demonstrating that, at least in metallo-proteins, the downhill mechanism can be found under a much wider range of conditions and coupled to other different transitions. We also show that mutations of Ros87 zinc coordination sphere produces a different folding scenario demonstrating that the organization of the metal ion core is determinant in the folding process of this family of proteins.
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http://dx.doi.org/10.1038/s41598-020-78008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713307PMC
December 2020

Lipid-Chaperone Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins.

ACS Chem Neurosci 2020 12 3;11(24):4336-4350. Epub 2020 Dec 3.

Department of Chemical Sciences, University of Catania, Catania 95124, Italy.

An increasing number of human diseases has been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer's, and Parkinson's, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal that this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and nonamyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a "lipid-chaperone" hypothesis as a unifying framework for protein-membrane poration.
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http://dx.doi.org/10.1021/acschemneuro.0c00588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769131PMC
December 2020

Substitution of the Native Zn(II) with Cd(II), Co(II) and Ni(II) Changes the Downhill Unfolding Mechanism of Ros87 to a Completely Different Scenario.

Int J Mol Sci 2020 Nov 5;21(21). Epub 2020 Nov 5.

Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania-Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.

The structural effects of zinc replacement by xenobiotic metal ions have been widely studied in several eukaryotic and prokaryotic zinc-finger-containing proteins. The prokaryotic zinc finger, that presents a bigger βββαα domain with a larger hydrophobic core with respect to its eukaryotic counterpart, represents a valuable model protein to study metal ion interaction with metallo-proteins. Several studies have been conducted on Ros87, the DNA binding domain of the prokaryotic zinc finger Ros, and have demonstrated that the domain appears to structurally tolerate Ni(II), albeit with important structural perturbations, but not Pb(II) and Hg(II), and it is in vitro functional when the zinc ion is replaced by Cd(II). We have previously shown that Ros87 unfolding is a two-step process in which a zinc binding intermediate converts to the native structure thorough a delicate downhill folding transition. Here, we explore the folding/unfolding behaviour of Ros87 coordinated to Co(II), Ni(II) or Cd(II), by UV-Vis, CD, DSC and NMR techniques. Interestingly, we show how the substitution of the native metal ion results in complete different folding scenarios. We found a two-state unfolding mechanism for Cd-Ros87 whose metal affinity is comparable to the one obtained for the native Zn-Ros87, and a more complex mechanism for Co-Ros87 and Ni-Ros87, that show higher values. Our data outline the complex cross-correlation between the protein-metal ion equilibrium and the folding mechanism proposing such an interplay as a key factor in the proper metal ion selection by a specific metallo-protein.
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http://dx.doi.org/10.3390/ijms21218285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663847PMC
November 2020

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.

The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri -methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators.
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http://dx.doi.org/10.3390/ijms21197190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582714PMC
September 2020

Modulating Aβ aggregation by tyrosol-based ligands: The crucial role of the catechol moiety.

Biophys Chem 2020 10 17;265:106434. Epub 2020 Jul 17.

Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4, I-80126 Napoli, Italy. Electronic address:

The abnormal deposition of Aβ amyloid deposits in the brain is a hallmark of Alzheimer's disease (AD). Based on this evidence, many current therapeutic approaches focus on the development of small molecules halting Aβ aggregation. However, due to the temporary and elusive structures of amyloid assemblies, the rational design of aggregation inhibitors remains a challenging task. Here we combine ThT assays and MD simulations to study Aβ aggregation in the presence of the natural compounds tyrosol (TY), 3-hydroxytyrosol (HDT), and 3-methoxytyrosol (homovanillyl alcohol - HVA). We show that albeit HDT is a potent inhibitor of amyloid growth, TY and HVA catalyze fibril formation. An inspection of MD simulations trajectories revealed that the different effects of these three molecules on Aβ aggregation are ascribable to their capacity to arrange H-bonds network between the ligand (position C-3) and the peptide (Glu22). We believe that our results may contribute to the design of more effective and safe small molecules able to contrast pathogenic amyloid aggregation.
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http://dx.doi.org/10.1016/j.bpc.2020.106434DOI Listing
October 2020

Trehalose Conjugates of Silybin as Prodrugs for Targeting Toxic Aβ Aggregates.

ACS Chem Neurosci 2020 09 5;11(17):2566-2576. Epub 2020 Aug 5.

Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Sede Secondaria di Catania, Via Paolo Gaifami 18, 95126 Catania, Italy.

Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (), has been shown to significantly inhibit Aβ aggregation and to exert neuroprotective properties . However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both Aβ monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of Aβ. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.
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http://dx.doi.org/10.1021/acschemneuro.0c00232DOI Listing
September 2020

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells.

Int J Mol Sci 2020 Apr 20;21(8). Epub 2020 Apr 20.

CNR Istituto di Cristallografia Sede Secondaria di Catania, Via Gaifami 18, 95126 Catania, Italy.

Copper plays an important role as a regulator in many pathologies involving the angiogenesis process. In cancerogenesis, tumor progression, and angiogenic diseases, copper homeostasis is altered. Although many details in the pathways involved are still unknown, some copper-specific ligands have been successfully used as therapeutic agents. Copper-binding peptides able to modulate angiogenesis represent a possible way to value new drugs. We previously reported that a fragment (VEGF73-101) of vascular endothelial growth factor (VEGF165), a potent angiogenic, induced an apoptotic effect on human umbilical vein endothelial cells. The aim of this study was to investigate the putative copper ionophoric activity of VEGF73-101, as well as establish a relationship between the structure of the peptide fragment and the cytotoxic activity in the presence of copper(II) ions. Here, we studied the stoichiometry and the conformation of the VEGF73-101/Cu(II) complexes and some of its mutated peptides by electrospray ionization mass spectrometry and circular dichroism spectroscopy. Furthermore, we evaluated the effect of all peptides in the absence and presence of copper ions by cell viability and cytofuorimetric assays. The obtained results suggest that VEGF73-101 could be considered an interesting candidate in the development of new molecules with ionophoric properties as agents in antiangiogenic therapeutic approaches.
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http://dx.doi.org/10.3390/ijms21082866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216235PMC
April 2020

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.

Biochim Biophys Acta Mol Basis Dis 2020 07 8;1866(7):165793. Epub 2020 Apr 8.

Dept of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis.
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http://dx.doi.org/10.1016/j.bbadis.2020.165793DOI Listing
July 2020

Symmetry-breaking transitions in the early steps of protein self-assembly.

Eur Biophys J 2020 Mar 2;49(2):175-191. Epub 2020 Mar 2.

Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy.

Protein misfolding and subsequent self-association are complex, intertwined processes, resulting in development of a heterogeneous population of aggregates closely related to many chronic pathological conditions including Type 2 Diabetes Mellitus and Alzheimer's disease. To address this issue, here, we develop a theoretical model in the general framework of linear stability analysis. According to this model, self-assemblies of peptides with pronounced conformational flexibility may become, under particular conditions, unstable and spontaneously evolve toward an alternating array of partially ordered and disordered monomers. The predictions of the theory were verified by atomistic molecular dynamics (MD) simulations of islet amyloid polypeptide (IAPP) used as a paradigm of aggregation-prone polypeptides (proteins). Simulations of dimeric, tetrameric, and hexameric human-IAPP self-assemblies at physiological electrolyte concentration reveal an alternating distribution of the smallest domains (of the order of the peptide mean length) formed by partially ordered (mainly β-strands) and disordered (turns and coil) arrays. Periodicity disappears upon weakening of the inter-peptide binding, a result in line with the predictions of the theory. To further probe the general validity of our hypothesis, we extended the simulations to other peptides, the Aβ(1-40) amyloid peptide, and the ovine prion peptide as well as to other proteins (SOD1 dimer) that do not belong to the broad class of intrinsically disordered proteins. In all cases, the oligomeric aggregates show an alternate distribution of partially ordered and disordered monomers. We also carried out Surface Enhanced Raman Scattering (SERS) measurements of hIAPP as an experimental validation of both the theory and in silico simulations.
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http://dx.doi.org/10.1007/s00249-020-01424-1DOI Listing
March 2020

Tau/Aβ chimera peptides: Evaluating the dual function of metal coordination and membrane interaction in one sequence.

J Inorg Biochem 2020 04 11;205:110996. Epub 2020 Jan 11.

Istituto di Cristallografia S.S. di Catania, Via P. Gaifami 18, 95126 Catania, Italy. Electronic address:

Several abnormal events may concur as major risk factors for Alzheimer's disease (AD) pathogenesis. For instance, dysregulation of brain's metal homeostasis and amyloid-mediated membrane damage are established toxic mechanisms causing neuronal death. In this study, we assess the amyloidogenic propensity and membrane-damage effects, either in the presence or in absence of metal ions, of two newly synthesized bifunctional peptides. These were designed to comprise a metal chelating N-terminus region derived from Tau protein namely the Tau9-16 (EVMEDHAG) or Tau26-33 (QGGYTMHQ) sequences, merged with the C-terminal hydrophobic region analogous to the Amyloid beta (Aβ) 16-20 aminoacid sequence KLVFF (KL). Comparative circular dichroism or fluorescence experiments were carried out to look at the peptide conformation, fibril formation and membrane affinity of Tau9-16KL and Tau26-33KL peptides. We found that Tau9-16KL and Tau26-33KL perturb the fibrillogenic process of Aβ. Furthermore Cu(II) and, to a lower extent, Zn(II) induced conformational changes Tau26-33KL both in water and in membrane-mimicking environment. By contrast, due to a different metal coordination mode we observed for Tau9-16KL an unstructured peptide conformation in all the experimental conditions. Unlike aqueous solution, a certain propensity to form amyloid structures at the lipid membrane interface clearly emerged for both the peptides. However, the two peptides exhibit a different capability to elicit membrane damage depending on the presence or absence of metal ions. Tau9-16KL and Tau26-33KL can be used as peptide-based molecular systems able to interfere with the metal dependent Aβ/Tau cross-seeded generation of membrane active amyloid species.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.110996DOI Listing
April 2020

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β-Amyloid Toxicity.

ChemMedChem 2020 02 17;15(3):302-316. Epub 2019 Dec 17.

Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via P. Gaifami 18, 95126, Catania, Italy.

Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an "open gate" mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α-ring surfaces and influencing gating dynamics. Docking studies coupled with STD-NMR experiments showed that H-bonds and π-π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α-ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH-SY5Y cells from β-amyloid (Aβ) toxicity. ESI-MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dose-dependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment.
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http://dx.doi.org/10.1002/cmdc.201900612DOI Listing
February 2020

Site directed mutagenesis of insulin-degrading enzyme allows singling out the molecular basis of peptidase versus E1-like activity: the role of metal ions.

Metallomics 2019 02;11(2):278-281

Institute of Biostructures and Bioimaging, National Research Council, Catania, Italy.

Four specifically designed IDE mutants have been used to unveil the molecular basis of peptidase versus E1-like activity of the enzyme. We have found that physiological concentrations of copper(ii) ions inhibit the proteolytic activity of the enzyme towards small and large substrates but have no effect on the E1-like activity of the enzyme.
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http://dx.doi.org/10.1039/c8mt00288fDOI Listing
February 2019

Phospholipids Critical Micellar Concentrations Trigger Different Mechanisms of Intrinsically Disordered Proteins Interaction with Model Membranes.

J Phys Chem Lett 2018 Sep 27;9(17):5125-5129. Epub 2018 Aug 27.

Department of Chemical Sciences , University of Catania , Viale A. Doria 6 , 95125 Catania , Italy.

Amyloidogenic proteins are involved in many diseases, including Alzheimer's, Parkinson's, and type II diabetes. These proteins are thought to be toxic for cells because of their abnormal interaction with the cell membrane. Simpler model membranes (LUVs) have been used to study the early steps of membrane-protein interactions and their subsequent evolution. Phospholipid LUVs formed in water solution establish a chemical equilibrium between self-assembled LUVs and a small amount of phospholipids in water solution (CMC). Here, using both experimental and molecular dynamics simulations approach we demonstrate that the insertion of IAPP, an amyloidogenic peptide involved in diabetes, in membranes is driven by free lipids in solution in dynamic equilibrium with the self-assembled lipids of the bilayer. It is suggested that this could be a general mechanism lying at the root of membrane insertion processes of self-assembling peptides.
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http://dx.doi.org/10.1021/acs.jpclett.8b02241DOI Listing
September 2018

Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins.

Chem Sci 2018 Apr 1;9(13):3290-3298. Epub 2018 Mar 1.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies , University of Campania "Luigi Vanvitelli" , Via Vivaldi 43 , 81100 Caserta , Italy . Email:

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml1 and zinc-lacking Ml4. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml1 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml4 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml4 and Ml1 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml1 has formed only amorphous aggregates and Ml4 is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases.
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http://dx.doi.org/10.1039/c8sc00166aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933289PMC
April 2018

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S.

Cell Mol Life Sci 2018 Sep 28;75(18):3441-3456. Epub 2018 Mar 28.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE) ≤ 30 nM and activating at (IDE) ≥ 30 nM. Only an activating effect is observed in a yeast mutant locked in the "open" conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S "open"-"closed" allosteric equilibrium. Protein-protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.
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http://dx.doi.org/10.1007/s00018-018-2807-yDOI Listing
September 2018

The active role of Ca ions in Aβ-mediated membrane damage.

Chem Commun (Camb) 2018 Apr;54(29):3629-3631

Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Sede Secondaria di Catania, Via Paolo Gaifami 18, 95126, Catania, Italy.

Calcium dysregulation, membrane leakage and Aβ amyloid growth are hallmarks of Alzheimer's disease. Here we show that Ca2+ ions inhibit membrane damage due to amyloid channels but enhance membrane disruption associated with fibers growing on the lipid surface. The similarities with IAPP suggest that this may represent a mechanism common to all proteinopathies.
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http://dx.doi.org/10.1039/c8cc01132jDOI Listing
April 2018

A blend of two resveratrol derivatives abolishes hIAPP amyloid growth and membrane damage.

Biochim Biophys Acta Biomembr 2018 Sep 17;1860(9):1793-1802. Epub 2018 Mar 17.

Istituto CNR di Biostrutture e Bioimmagini- Sede Secondaria di Catania, Via Paolo Gaifami 18, 95126 Catania, Italy. Electronic address:

Type II diabetes mellitus (T2DM) is characterized by the presence of amyloid deposits of the human islet amyloid polypeptide (hIAPP) in pancreatic β-cells. A wealth of data supports the hypothesis that hIAPP's toxicity is related to an abnormal interaction of amyloids with islet cell membranes. Thus, many studies aimed at finding effective therapies for T2DM focus on the design of molecules that are able to inhibit hIAPP's amyloid growth and the related membrane damage as well. Based on this view and inspired by its known anti-amyloid properties, we have functionalized resveratrol with a phosphoryl moiety (4'-O-PR) that improves its solubility and pharmacological properties. A second resveratrol derivative has also been obtained by conjugating resveratrol with a dimyristoylphosphatidyl moiety (4'-DMPR). The use of both compounds resulted in abolishing both amyloid growth and amyloid mediated POPC/POPS membrane damage in tube tests. We propose that a mixture of a water-soluble anti-aggregating compound and its lipid-anchored derivative may be employed as a general strategy to prevent and/or to halt amyloid-related membrane damage.
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http://dx.doi.org/10.1016/j.bbamem.2018.03.012DOI Listing
September 2018

Amyloid growth and membrane damage: Current themes and emerging perspectives from theory and experiments on Aβ and hIAPP.

Biochim Biophys Acta Biomembr 2018 Sep 1;1860(9):1625-1638. Epub 2018 Mar 1.

Università degli Studi di Catania, Dipartimento di Scienze Chimiche, Viale Andrea Doria 6, 95125 Catania, Italy. Electronic address:

Alzheimer's Disease (AD) and Type 2 diabetes mellitus (T2DM) are two incurable diseases both hallmarked by an abnormal deposition of the amyloidogenic peptides Aβ and Islet Amyloid Polypeptide (IAPP) in affected tissues. Epidemiological data demonstrate that patients suffering from diabetes are at high risk of developing AD, thus making the search for factors common to the two pathologies of special interest for the design of new therapies. Accumulating evidence suggests that the toxic properties of both Aβ or IAPP are ascribable to their ability to damage the cell membrane. However, the molecular details describing Aβ or IAPP interaction with membranes are poorly understood. This review focuses on biophysical and in silico studies addressing these topics. Effects of calcium, cholesterol and membrane lipid composition in driving aberrant Aβ or IAPP interaction with the membrane will be specifically considered. The cross correlation of all these factors appears to be a key issue not only to shed light in the countless and often controversial reports relative to this area but also to gain valuable insights into the central events leading to membrane damage caused by amyloidogenic peptides. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.
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http://dx.doi.org/10.1016/j.bbamem.2018.02.022DOI Listing
September 2018

Strategy to discover full-length amyloid-beta peptide ligands using high-efficiency microarray technology.

Beilstein J Nanotechnol 2017 20;8:2446-2453. Epub 2017 Nov 20.

IMM-CNR, Catania, Italy.

Although the formation of β-amyloid (Aβ) fibrils in neuronal tissues is a hallmark of Alzheimer disease (AD), small-sized Aβ oligomers rather than mature fibrils have been identified as the most neurotoxic species. Therefore, the design of new inhibitors, able to prevent the aggregation of Aβ, is believed to be a promising therapeutic approach to AD. Unfortunately, the short-lived intermediate structures that occur in a solution along the Aβ aggregation pathway escape conventional experimental investigations and there is urgent need of new tools aimed at the discovery of agents targeting monomeric Aβ and blocking the early steps of amyloid aggregation. Here, we show the combination of high-efficiency slides (HESs) with peptide microarrays as a promising tool for identifying small peptides that bind Aβ monomers. To this aim, HESs with two immobilized reference peptides, (i.e., KLVFF and Semax) with opposite behavior, were investigated for binding to fluorescently labeled Aβ peptide. Transmission electron microscopy was used to demonstrate Aβ fibrillar aggregates missing. The use of HESs was critical to ensure convenient output of the fluorescent microarrays. The resulting sensitivity, as well as the low sample consumption and the high potential for miniaturization, suggests that the proposed combination of peptide microarrays and highly efficient slides would be a very effective technology for molecule profiling in AD drug discovery.
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http://dx.doi.org/10.3762/bjnano.8.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704750PMC
November 2017

Electrostatic Map Of Proteasome α-Rings Encodes The Design of Allosteric Porphyrin-Based Inhibitors Able To Affect 20S Conformation By Cooperative Binding.

Sci Rep 2017 12 6;7(1):17098. Epub 2017 Dec 6.

Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Via Montpellier 1, 00133, Roma, Italy.

The importance of allosteric proteasome inhibition in the treatment of cancer is becoming increasingly evident. Motivated by this urgent therapeutic need, we have recently identified cationic porphyrins as a highly versatile class of molecules able to regulate proteasome activity by interfering with gating mechanisms. In the present study, the mapping of electrostatic contacts bridging the regulatory particles with the α-rings of the human 20S proteasome led us to the identification of (meso-tetrakis(4-N-methylphenyl pyridyl)-porphyrin (pTMPyPP4) as a novel non-competitive inhibitor of human 20S proteasome. pTMPyPP4 inhibition mechanism implies a positive cooperative binding to proteasome, which disappears when a permanently open proteasome mutant (α-3ΔN) is used, supporting the hypothesis that the events associated with allosteric proteasome inhibition by pTMPyPP4 interfere with 20S gating and affect its "open-closed" equilibrium. Therefore, we propose that the spatial distribution of the negatively charged residues responsible for the interaction with regulatory particles at the α-ring surface of human 20S may be exploited as a blueprint for the design of allosteric proteasome regulators.
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http://dx.doi.org/10.1038/s41598-017-17008-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719074PMC
December 2017

Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer's disease and other tauopathies.

Oncotarget 2017 Sep 22;8(39):64745-64778. Epub 2017 Apr 22.

European Brain Research Institute, Rome, Italy.

The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH -derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer's disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH tau 26-44 (aka NH htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K -evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.
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http://dx.doi.org/10.18632/oncotarget.17371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630290PMC
September 2017

Amino- and chloro-8-hydroxyquinolines and their copper complexes as proteasome inhibitors and antiproliferative agents.

Metallomics 2017 10;9(10):1439-1446

Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.

Proliferation and programmed cell death are tightly correlated with the ubiquitin-proteasome system (UPS). Alterations in the UPS may be implicated in pathological conditions such as the proteasome over-activity in cancer cells. Mounting evidence indicates that many types of actively proliferating malignant cells are more sensitive to proteasome inhibition than normal cells, and therefore UPS inhibitors are actively pursued as anticancer agents. The approval of the proteasome inhibitor drug bortezomib for the treatment of myeloma and lymphoma further highlights the need for UPS inhibitors. Recent studies have suggested that clioquinol and 5-amino-8-hydroxyquinoline can inhibit proteasome activity and induce apoptosis in human cancer cells. As for clioquinol, a copper-dependent and -independent mechanism has been proposed to explain the inhibition of the proteasome whereas the activity of 5-amino-8-hydroxyquinoline has not been explored in the presence of copper(ii) ions. Herein, we investigated the biological activity of some 8-hydroxyquinolines by using human ovarian (A2780) and lung (A549) cancer cells. The effect of copper(ii) on the activity of these compounds was also evaluated. The investigated systems inhibit the chymotrypsin-like activity of the proteasome and induce growth inhibition and apoptosis in a concentration-dependent manner. Copper(ii) ions increase the activity of 8-hydroxyquinoline derivatives except in the case of 5-amino-8-hydroxyquinoline. This study suggests the great potential of amino- and chloro-8-hydroxyquinolines as anticancer agents. Furthermore, it clarifies some aspects concerning the activity of 5-amino-8-hydroxyquinoline, which has been previously proposed as a proteasome inhibitor capable of overcoming resistance to bortezomib.
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http://dx.doi.org/10.1039/c7mt00156hDOI Listing
October 2017

New comprehensive studies of a gold(III) Dithiocarbamate complex with proven anticancer properties: Aqueous dissolution with cyclodextrins, pharmacokinetics and upstream inhibition of the ubiquitin-proteasome pathway.

Eur J Med Chem 2017 Sep 19;138:115-127. Epub 2017 Jun 19.

Università degli Studi di Padova, Dipartimento di Scienze Chimiche, Via F. Marzolo 1, 35131, Padova, Italy. Electronic address:

The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy-kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of α-cyclodextrins (CDs), namely β-CD, Me-β-CD and HP-β-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-β-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a t of few minutes and a slow escretion (t of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP-β-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin-proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes.
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http://dx.doi.org/10.1016/j.ejmech.2017.06.013DOI Listing
September 2017

Multiple functions of insulin-degrading enzyme: a metabolic crosslight?

Crit Rev Biochem Mol Biol 2017 10 21;52(5):554-582. Epub 2017 Jun 21.

a Department of Clinical Sciences and Translation Medicine , University of Roma Tor Vergata , Roma , Italy.

Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the "aggregopathies" and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin-proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the "quality control" machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.
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http://dx.doi.org/10.1080/10409238.2017.1337707DOI Listing
October 2017

Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry.

ACS Chem Neurosci 2017 08 9;8(8):1767-1778. Epub 2017 Jun 9.

Institute of Biostructures and Bioimages-Catania, National Research Council, Via Paolo Gaifami 8, 95126 Catania, Italy.

The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment MVGGVV of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments LVFF and NKGAII of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment LVFF but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.
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http://dx.doi.org/10.1021/acschemneuro.7b00110DOI Listing
August 2017

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

Curr Med Chem 2018 Feb;25(4):525-539

Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Catania, Italy.

Background: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration.

Methods: Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs.

Results: Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease.

Conclusions: In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials.
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http://dx.doi.org/10.2174/0929867324666170518094404DOI Listing
February 2018
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