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Guanine-rich sequences of nucleic acids, including DNA and RNA, are known to fold into non-canonical structures named G-quadruplexes (G4s). Such arrangements of these macromolecular polymers are mainly located in telomeres and in promoter regions of oncogenes and, for this reason, they represent a potential target for compounds with therapeutic applications. In fact, the ligand-mediated stabilization of G4s inhibits telomerase and the activity of transcriptional machinery and counteracts cancer cell immortalization. Flavonoids, along with other classes of small molecules, have been previously tested for their ability to stabilize G4s, but the mechanism of their interaction has not been fully elucidated. In the current work, we report a multi-technique investigation on the binding of tosylated isoflavones obtained by the B-ring modification of compounds from Maclura pomifera to a telomeric DNA sequence. Our study demonstrates that such derivatization leads to compounds showing lower binding affinity but with an increased selectivity toward G4 with respect to double-stranded DNA. The binding mode to the macromolecular target G4 was studied by combining results from electrospray mass spectrometry binding studies, nuclear magnetic resonance experiments and computational simulations. Overall, our findings show that tosylation influences the selectivity toward the macromolecular target by affecting the interaction mode with the nucleic acid. [ABSTRACT FROM AUTHOR]

Gamma-oryzanol (ORY), found in rice (Oryza sativa L.), is a mixture of ferulic acid esters with triterpene alcohols, well-known for its antioxidant and anti-inflammatory properties. Our past research demonstrated its positive impact on cognitive function in adult mice, influencing synaptic plasticity and neuroprotection. In this study, we explored whether ORY can exert neuro-differentiating effects by using different experimental models. For this purpose, chemical characterization identified four components that are most abundant in ORY. In human neuroblastoma cells, we showed ORY's ability to stimulate neurite outgrowth, upregulating the expression of GAP43, BDNF, and TrkB genes. In addition, ORY was found to guide adult mouse hippocampal neural progenitor cells (NPCs) toward a neuronal commitment. Microinjection of ORY in zebrafish Tg (-3.1 neurog1:GFP) amplified neurog1-GFP signal, islet1, and bdnf mRNA levels. Zebrafish nrf2a and nrf2b morphants (MOs) were utilized to assess ORY effects in the presence or absence of Nrf2. Notably, ORY's ability to activate bdnf was nullified in nrf2a-MO and nrf2b-MO. Furthermore, computational analysis suggested ORY's single components have different affinities for the Keap1-Kelch domain. In conclusion, although more in-depth studies are needed, our findings position ORY as a potential source of bioactive molecules with neuro-differentiating potential involving the Nrf2 pathway. [ABSTRACT FROM AUTHOR]

The development of inhibitors that target the papain‐like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent causing coronavirus disease 2019 (COVID‐19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS‐CoV‐2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a μM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization. [ABSTRACT FROM AUTHOR]

In drug discovery, ligand-mediated stabilization of G-quadruplexes is pursued for regulating gene expression and key cellular processes. Electrospray ionization mass spectrometry (ESI-MS) has been optimized for screening putative DNA-binding small molecules of natural and synthetic origin. Several flavonoids were reported to interact with G-quadruplex, and quercetin is among them. In this contribution, the interaction with G-quadruplex DNA of rutin, a glycoside of quercetin extracted from flower buds of Styphnolobium japonicum (L.) Schott, was investigated by means of ESI-MS and molecular docking. While rutin and quercetin showed similar G-quadruplex binding affinity values, rutin was characterized by enhanced selectivity for G-quadruplex over double stranded DNA. Moreover, collision-induced dissociation (CID) assays demonstrated that rutin stabilizes the G-quadruplex arrangement more efficiently, and molecular docking predicted stacking as the preferential interaction pattern. [ABSTRACT FROM AUTHOR]

Natural and synthetic small molecules targeting G-quadruplex are currently being studied. These peculiar DNA arrangements arise in guanine-rich sequences located in telomeres, oncogene promoters and in several viruses. Two semi-synthetic derivatives of osajin, a natural isoflavone from Maclura pomifera, were prepared and screened for their binding affinity towards G-quadruplex and double stranded DNA (dsDNA) using electrospray mass spectrometry (ESI-MS). Although an overall decrease in affinity for DNA was observed, one of the derivatives showed improved selectivity for G-quadruplex over dsDNA, retaining structure stabilization properties. Binding motif was studied by collision-induced dissociation (CID) assays and molecular docking, that suggested stacking as the preferential interaction pattern. Moreover, the compound selectively induced DNA damage on the G-quadruplex sequence upon UV irradiation, due to the presence of the photoreactive aryl tosylate group. [ABSTRACT FROM AUTHOR]

G-quadruplex DNA stabilization mediated by small molecules is an attractive approach to modulate the transcription of guanine-rich sequences and contrast unregulated cell proliferation. Natural alkaloids have been reported to target this macromolecular arrangement, and such mechanism may be among these underlying the antiproliferative effect of some flavonoids. The binding affinity for G-quadruplex and double stranded DNA of 4 isoflavones from Maclura pomifera, namely osajin, pomiferin, scandenone and auriculasin, was evaluated using electrospray mass spectrometry (ESI-MS). The experiments pointed out that osajin and scandenone preferentially bind G-quadruplex. Moreover, since G-quadruplex stabilization is a crucial aim for triggering biological effects such as gene expression, collision-induced dissociation (CID) assays were performed to study the relative gas-phase kinetic stability of the DNA/ligand complexes. Osajin was identified as the best G-quadruplex stabilizer of the set, and in silico docking studies indicate that stacking is the preferred interaction motif of this natural compound. [ABSTRACT FROM AUTHOR]

In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set. [ABSTRACT FROM AUTHOR]