scholarly journals G-Quadruplex-Helicase Interactions and the Impact of Small Molecules

2019 ◽  
Vol 116 (3) ◽  
pp. 39a
Author(s):  
Parastoo Maleki ◽  
Hamza Balci
Keyword(s):  
Small Molecules ◽  
G Quadruplex ◽  
The Impact

scholarly journals Impact of Small Molecules on Intermolecular G-Quadruplex Formation

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1570 ◽  
Author(s):  
Prabesh Gyawali ◽  
Keshav GC ◽  
Yue Ma ◽  
Sanjaya Abeysirigunawardena ◽  
Kazuo Nagasawa ◽  
...  
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
The Other ◽  
Single Molecule Level ◽  
G Quadruplex ◽  
Dna Strands ◽  
Order Of Magnitude ◽  
Single Molecule Studies ◽  
Quadruplex Formation ◽  
The Impact

We performed single molecule studies to investigate the impact of several prominent small molecules (the oxazole telomestatin derivative L2H2-6OTD, pyridostatin, and Phen-DC3) on intermolecular G-quadruplex (i-GQ) formation between two guanine-rich DNA strands that had 3-GGG repeats in one strand and 1-GGG repeat in the other (3+1 GGG), or 2-GGG repeats in each strand (2+2 GGG). Such structures are not only physiologically significant but have recently found use in various biotechnology applications, ranging from DNA-based wires to chemical sensors. Understanding the extent of stability imparted by small molecules on i-GQ structures, has implications for these applications. The small molecules resulted in different levels of enhancement in i-GQ formation, depending on the small molecule and arrangement of GGG repeats. The largest enhancement we observed was in the 3+1 GGG arrangement, where i-GQ formation increased by an order of magnitude, in the presence of L2H2-6OTD. On the other hand, the enhancement was limited to three-fold with Pyridostatin (PDS) or less for the other small molecules in the 2+2 GGG repeat case. By demonstrating detection of i-GQ formation at the single molecule level, our studies illustrate the feasibility to develop more sensitive sensors that could operate with limited quantities of materials.

Nanoporous Gold Disks Functionalized with Stabilized G-Quadruplex Moieties for Sensing Small Molecules

2016 ◽  
Vol 8 (44) ◽  
pp. 29968-29976 ◽  
Author(s):  
Suyan Qiu ◽  
Fusheng Zhao ◽  
Oussama Zenasni ◽  
Jingting Li ◽  
Wei-Chuan Shih
Keyword(s):  
Small Molecules ◽  
Nanoporous Gold ◽  
G Quadruplex

scholarly journals Erratum: Corrigendum: Structural revisions of small molecules reported to cross-link G-quadruplex DNA in vivo reveal a repetitive assignment error in the literature

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Paul E. Reyes-Gutiérrez ◽  
Tomáš Kapal ◽  
Blanka Klepetářová ◽  
David Šaman ◽  
Radek Pohl ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cross Link ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Assignment Error

scholarly journals Selective Binding of Distamycin A Derivative to G-Quadruplex Structure [d(TGGGGT)]4

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Bruno Pagano ◽  
Iolanda Fotticchia ◽  
Stefano De Tito ◽  
Carlo A. Mattia ◽  
Luciano Mayol ◽  
...  
Keyword(s):  
Small Molecules ◽  
Titration Calorimetry ◽  
Distamycin A ◽  
Structural Modifications ◽  
Telomerase Inhibitors ◽  
G Quadruplex ◽  
Nmr Techniques ◽  
Eukaryotic Organisms ◽  
New Anticancer Drugs ◽  
Binding Behaviour

Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G-quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound1) and the [d(TGGGGT)]4quadruplex. Additionally, to compare the binding behaviour of netropsin and compound1to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)]4has been performed. Experiments show that netropsin and compound1are able to bind to [d(TGGGGT)]4with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound1decrease the affinity of the ligand toward the duplex, enhancing the selectivity.

scholarly journals G-Quadruplex-Based Drug Delivery Systems for Cancer Therapy

2021 ◽  
Vol 14 (7) ◽  
pp. 671
Author(s):  
Jéssica Lopes-Nunes ◽  
Paula Oliveira ◽  
Carla Cruz
Keyword(s):  
Drug Delivery ◽  
Small Molecules ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Nano Particles ◽  
Future Research ◽  
High Affinity ◽  
Dna And Rna ◽  
G Quadruplex ◽  
Gold Nano Particles

G-quadruplexes (G4s) are a class of nucleic acids (DNA and RNA) with single-stranded G-rich sequences. Owing to the selectivity of some G4s, they are emerging as targeting agents to overtake side effects of several potential anticancer drugs, and delivery systems of small molecules to malignant cells, through their high affinity or complementarity to specific targets. Moreover, different systems are being used to improve their potential, such as gold nano-particles or liposomes. Thus, the present review provides relevant data about the different studies with G4s as drug delivery systems and the challenges that must be overcome in the future research.

Predictability of Elimination and Excretion of Small Molecules from Animals to Humans, and Impact on Dosimetry for human ADME Studies with Radiolabeled Drugs

2021 ◽  
Vol 16 ◽  
Author(s):  
Ad Roffel ◽  
Jan Jaap van Lier ◽  
Gerk Rozema ◽  
Ewoud-Jan van Hoogdalem
Keyword(s):  
Small Molecules ◽  
Half Life ◽  
Fecal Excretion ◽  
Radiation Burden ◽  
Quantitative Correlation ◽  
Elimination Half ◽  
The Impact ◽  
Plasma Half Life ◽  
Entire Dataset ◽  
Actual Radiation

Background: We assessed the extent to which urinary and fecal excretion of 14C-labeled drug material in animal ADME studies was predictive of human ADME studies. We compared observed plasma elimination half lives for total drug related radioactivity in humans to pre-study predictions, and we estimated the impact of any major differences on human dosimetry calculations. Methods: We included 34 human ADME studies with doses of 14C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans versus animals; observed half life in humans versus predicted pre-study) and output parameters (effective dose post-study versus pre study) and assessed their relationship. Results: A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of 14C excreted in feces and the ratios of dosimetry outcomes in the entire dataset, but a statistically significant correlation was found when assessing the studies that were based on ICRP 60/62 (n=19 studies; P=0.0028). There also appeared to be a correlation between the plasma half-life ratios and the ratios of dosimetry results. A quantitative correlation assessment showed that there was a statistically significant correlation between these ratios (P<0.0001). Conclusion: In all cases where the plasma elimination half-life for 14C in humans was found to be longer than the predicted value, the radiation burden was still within ICRP Category IIa. Containment of the actual radiation burden below the limit of 1.00 mSv appeared to be determined partly also by our choice to limit 14C doses to 3.7 MBq.

scholarly journals G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 304 ◽  
Author(s):  
Roberta Amato ◽  
Martina Valenzuela ◽  
Francesco Berardinelli ◽  
Erica Salvati ◽  
Carmen Maresca ◽  
...  
Keyword(s):  
Dna Damage ◽  
Sister Chromatid Exchanges ◽  
Telomere Maintenance ◽  
Osteosarcoma Cell ◽  
Telomeric Dna ◽  
Replicative Stress ◽  
Alternative Lengthening ◽  
G Quadruplex ◽  
Reduce Cell Proliferation ◽  
The Impact

Most human tumors maintain telomere lengths by telomerase, whereas a portion of them (10–15%) uses a mechanism named alternative lengthening of telomeres (ALT). The telomeric G-quadruplex (G4) ligand RHPS4 is known for its potent antiproliferative effect, as shown in telomerase-positive cancer models. Moreover, RHPS4 is also able to reduce cell proliferation in ALT cells, although the influence of G4 stabilization on the ALT mechanism has so far been poorly investigated. Here we show that sensitivity to RHPS4 is comparable in ALT-positive (U2OS; SAOS-2) and telomerase-positive (HOS) osteosarcoma cell lines, unlinking the telomere maintenance mechanism and RHPS4 responsiveness. To investigate the impact of G4 stabilization on ALT, the cardinal ALT hallmarks were analyzed. A significant induction of telomeric doublets, telomeric clusterized DNA damage, ALT-associated Promyelocytic Leukaemia-bodies (APBs), telomere sister chromatid exchanges (T-SCE) and c-circles was found exclusively in RHPS4-treated ALT cells. We surmise that RHPS4 affects ALT mechanisms through the induction of replicative stress that in turn is converted in DNA damage at telomeres, fueling recombination. In conclusion, our work indicates that RHPS4-induced telomeric DNA damage promotes overactivation of telomeric recombination in ALT cells, opening new questions on the therapeutic employment of G4 ligands in the treatment of ALT positive tumors.

scholarly journals Susceptibility of protein therapeutics to spontaneous chemical modifications by oxidation, cyclization, and elimination reactions

Amino Acids ◽  
2019 ◽  
Vol 51 (10-12) ◽  
pp. 1409-1431 ◽  
Author(s):  
Luigi Grassi ◽  
Chiara Cabrele
Keyword(s):  
Small Molecules ◽  
Three Dimensional ◽  
Drug Market ◽  
Structure And Function ◽  
Dimensional Structure ◽  
Chemical Modifications ◽  
Small Molecule Drugs ◽  
And Function ◽  
The Impact

Abstract Peptides and proteins are preponderantly emerging in the drug market, as shown by the increasing number of biopharmaceutics already approved or under development. Biomolecules like recombinant monoclonal antibodies have high therapeutic efficacy and offer a valuable alternative to small-molecule drugs. However, due to their complex three-dimensional structure and the presence of many functional groups, the occurrence of spontaneous conformational and chemical changes is much higher for peptides and proteins than for small molecules. The characterization of biotherapeutics with modern and sophisticated analytical methods has revealed the presence of contaminants that mainly arise from oxidation- and elimination-prone amino-acid side chains. This review focuses on protein chemical modifications that may take place during storage due to (1) oxidation (methionine, cysteine, histidine, tyrosine, tryptophan, and phenylalanine), (2) intra- and inter-residue cyclization (aspartic and glutamic acid, asparagine, glutamine, N-terminal dipeptidyl motifs), and (3) β-elimination (serine, threonine, cysteine, cystine) reactions. It also includes some examples of the impact of such modifications on protein structure and function.

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