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Apolipoprotein E in Alzheimer’s Disease
Full text linkThe pathophysiology of Alzheimer’s disease (AD) is related with the ongoing deterioration of brain lipid homeostasis, in which
the cholesterol transporter apolipoprotein E (APOE) plays a key role. Plasma protein APOE might be additionally associated with AD
due to its capability to bind the amyloid protein. There are three principal isoforms: APOE2, APOE3 and APOE4, encoded by three
different alleles (ε2, ε3, ε4). Among them, APOE4 is recognized as the toxic form involved in AD development and progression. In fact,
the presence of the ε4 allele correlates to an increase of about three times in the risk of developing the disease in late onset forms,
both familiar and sporadic. For this reason, APOE4 has been often highlighted as a promising therapeutic target. Nevertheless, recent
studies also suggest that the reduction of APOE protein levels, regardless of the isoform present, might be beneficial to deal with AD
progression.
Herein we report a brief overview of the proposed roles of APOE and in particular of ApoE4 in the insurgence and development
of AD. In particular, its intervention in amyloid-β dependent and independent processes are examined. New therapeutic approaches
for AD exploiting APOE as a target are finally discussed
Synthesis of tetrazole- and imidazole-based compounds: prophetic molecules made real for biological studies
No full textThe synthesis of tetrazole- and imidazole-based derivatives has been achieved via sulfur nucleophilic ringopening
of 2-oxiranyl-alcohols or chlorides. The derivatives obtained may represent interesting new chemical
tools to investigate biological functions and in particular the mitochondrial molecular chaperone TRAP1. The
results are discussed in the light of the availability of these molecules according to the proposed synthetic
procedures
Novel Therapeutic Horizons: SNCA Targeting in Parkinson’s Disease
No full textAlpha-synuclein (αSyn) aggregates are the primary component of Lewy bodies, which are pathological hallmarks of Parkinson’s disease (PD). The toxicity of αSyn seems to increase with its elevated expression during injury, suggesting that therapeutic approaches focused on reducing αSyn burden in neurons could be beneficial. Additionally, studies have shown higher levels of SNCA mRNA in the midbrain tissues and substantia nigra dopaminergic neurons of sporadic PD post-mortem brains compared to controls. Therefore, the regulation of SNCA expression and inhibition of αSyn synthesis could play an important role in the pathogenesis of injury, resulting in an effective treatment approach for PD. In this context, we summarized the most recent and innovative strategies proposed that exploit the targeting of SNCA to regulate translation and efficiently knock down cytoplasmatic levels of αSyn. Significant progress has been made in developing antisense technologies for treating PD in recent years, with a focus on antisense oligonucleotides and short-interfering RNAs, which achieve high specificity towards the desired target. To provide a more exhaustive picture of this research field, we also reported less common but highly innovative strategies, including small molecules, designed to specifically bind 5′-untranslated regions and, targeting secondary nucleic acid structures present in the SNCA gene, whose formation can be modulated, acting as a transcription and translation control. To fully describe the efficiency of the reported strategies, the effect of αSyn reduction on cellular viability and dopamine homeostasis was also considered
Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds
Full text linkNowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles-five-membered aromatic rings-emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially on 1,2,4 and 1,3,4 regioisomers. In the last years, an increasing number of oxadiazole derivatives, with remarkable cytotoxicity for several tumor lines, were identified. Structural modifications, that ensure higher cytotoxicity towards malignant cells, represent a solid starting point in the development of novel oxadiazole-based drugs. To increase the specificity of this strategy, outstanding oxadiazole scaffolds have been designed to selectively interact with biological targets, including enzymes, globular proteins, and nucleic acids, showing more promising antitumor effects. In the present work, we aim to provide a comprehensive overview of the anticancer activity of these heterocycles, describing their effect on different targets and highlighting how their structural versatility has been exploited to modulate their biological properties
Role of Copper and Zinc Ions in the Hydrolytic Degradation of Neurodegeneration-Related Peptides
No full textSpontaneous cleavage reactions normally occur in vivo on amino acid peptide backbones, leading to fragmentation products that can have different physiological roles and toxicity, particularly when the substrate of the hydrolytic processes are neuronal peptides and proteins highly related to neurodegeneration. We report a hydrolytic study performed with the HPLC-MS technique at different temperatures (4 °C and 37 °C) on peptide fragments of different neuronal proteins (amyloid-β, tau, and α-synuclein) in physiological conditions in the presence of Cu2+ and Zn2+ ions, two metal ions found at millimolar concentrations in amyloid plaques. The coordination of these metal ions with these peptides significantly protects their backbones toward hydrolytic degradation, preserving the entire sequences over two weeks in solution, while the free peptides in the same buffer are fully fragmented after the same or even shorter incubation period. Our data show that peptide cleavage is not only ruled by the chemical sensitivity of amino acids, but the peptide conformation changes induced by metal coordination influence hydrolytic reactions. The enhanced stability of neuronal peptides provided by metal coordination can increase local levels of amyloidogenic species capable of seeding fibril growth, resulting in aberrant protein depositions and deficits in neuronal activity
Structure–Activity Study on Substituted, Core-Extended, and Dyad Naphthalene Diimide G-Quadruplex Ligands Leading to Potent Antitrypanosomal Agents
No full text: Several G-quadruplex nucleic acid (G4s) ligands have been developed seeking target selectivity in the past decade. Naphthalene diimide (NDI)-based compounds are particularly promising due to their biological activity and red-fluorescence emission. Previously, we demonstrated the existence of G4s in the promoter region of parasite genomes, assessing the effectiveness of NDI-derivatives against them. Here, we explored the biological activity of a small library of G4-DNA ligands, exploiting the NDI pharmacophore, against both Trypanosoma brucei and Leishmania major parasites. Biophysical and biological assays were conducted. Among the various families analyzed, core-extended NDIs exhibited the most promising results concerning the selectivity and antiparasitic effects. NDI 16 emerged as the most potent, with an IC50 of 0.011 nM against T. brucei and remarkable selectivity vs MRC-5 cells (3454-fold). Fascinating, 16 is 480-fold more potent than the standard drug pentamidine (IC50 = 5.3 nM). Cellular uptake and parasite localization were verified by exploiting core-extended NDI red-fluorescent emission
Copper-Aβ Peptides and Oxidation of Catecholic Substrates: Reactivity and Endogenous Peptide Damage
No full textThe oxidative reactivity of copper complexes with
Ab peptides 1–16 and 1–28 (Ab16 and Ab28) against dopamine
and related catechols under physiological conditions
has been investigated in parallel with the competitive oxidative
modification undergone by the peptides. It was found
that both Ab16 and Ab28 markedly increase the oxidative
reactivity of copper(II) towards the catechol compounds, up
to a molar ratio of about 4:1 of peptide/copper(II). Copper
redox cycling during the catalytic activity induces the competitive
modification of the peptide at selected amino acid
residues. The main modifications consist of oxidation of
His13/14 to 2-oxohistidine and Phe19/20 to ortho-tyrosine,
and the formation of a covalent His6-catechol adduct. Competition
by the endogenous peptide is rather efficient, as approximately
one peptide molecule is oxidized every 10 molecules
of 4-methylcatechol
Naphthalene Diimide–Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action
Full text linkHuman immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multi-targeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)-tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified and tested the metal-free NDI-tetraazacycloalkane conjugate and the two derived metal-organic complexes (MOCs) that incorporate Cu2+ and Zn2+. The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 co-receptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 co-receptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve overall patient outcome
Selective light-up of dimeric G-quadruplex forming aptamers for efficient VEGF165 detection
No full textTo develop efficient anticancer theranostic systems, we studied the interaction between a cyanine dye, analogue of thiazole orange (named CyOH), and two G-quadruplex-forming aptamers, V7t1 and 3R02, recognizing the Vascular Endothelial Growth Factor 165 (VEGF165) - an angiogenic protein overexpressed in cancer cells, responsible for the rapid growth and metastases of solid tumours. We demonstrated, by exploiting different biophysical techniques - i.e. gel electrophoresis, circular dichroism (CD), UV-vis and fluorescence spectroscopy - that this cyanine interacted with both aptamers giving a marked fluorescence light-up only when bound to their dimeric forms. Interestingly, both oligonucleotides recognized VEGF165 with higher affinity when adopting dimeric G-quadruplexes, largely prevalent over their monomeric forms in pseudo-physiological conditions. Notably, the fluorescence light-up produced by the probe was maintained when the dimeric aptamer-CyOH complexes bound to the target protein. These complexes, tested on MCF-7 cancer cells using non-tumorigenic MCF-10A cells as control, were effectively internalized in cells and colocalized with a fluorescently-labelled anti-VEGF-A antibody, allowing both recognition and detection of the target. Our experiments showed that the studied systems are promising tools for anticancer theranostic strategies, combining the therapeutic potential of the G4-forming anti-VEGF aptamers with the diagnostic efficacy of the cyanine selective fluorescence light-up
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