Selective targeting of mutually exclusive DNA G-quadruplexes: HIV-1 LTR as paradigmatic model

Abstract Targeting of G-quadruplexes, non-canonical conformations that form in G-rich regions of nucleic acids, has been proposed as a novel therapeutic strategy toward several diseases, including cancer and infections. The unavailability of highly selective molecules targeting a G-quadruplex of choice has hampered relevant applications. Herein, we describe a novel approach, based on naphthalene diimide (NDI)-peptide nucleic acid (PNA) conjugates, taking advantage of the cooperative interaction of the NDI with the G-quadruplex structure and hybridization of the PNA with the flanking region upstream or downstream the targeted G-quadruplex. By biophysical and biomolecular assays, we show that the NDI-PNA conjugates are able to specifically recognize the G-quadruplex of choice within the HIV-1 LTR region, consisting of overlapping and therefore mutually exclusive G-quadruplexes. Additionally, the conjugates can induce and stabilize the least populated G-quadruplex at the expenses of the more stable ones. The general and straightforward design and synthesis, which readily apply to any G4 target of choice, together with both the red-fluorescent emission and the possibility to introduce cellular localization signals, make the novel conjugates available to selectively control G-quadruplex folding over a wide range of applications.

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Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents

Frontiers in Chemistry ◽

10.3389/fchem.2021.630357 ◽

2021 ◽

Vol 9 ◽

Author(s):

M. Shaheer Malik ◽

Syed Farooq Adil ◽

Ziad Moussa ◽

Hatem M. Altass ◽

Ismail I. Althagafi ◽

...

Keyword(s):

Rational Design ◽

Thermal Denaturation ◽

Telomeric Dna ◽

Docking Analysis ◽

Design And Synthesis ◽

Naphthalene Diimide ◽

G Quadruplex ◽

Further Development ◽

Molecular Docking Analysis ◽

Better Than

A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these hybrids experimentally, followed by evaluation of their ability to cause thermal denaturation of DNA and cytotoxic properties along with ADME predictions. The obtained results provided useful insights and two potential molecules were identified for further development.

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Recognition of an important G-quadruplex in the HIV-1 promoter with natural small molecules

Canadian Journal of Chemistry ◽

10.1139/cjc-2015-0215 ◽

2016 ◽

Vol 94 (1) ◽

pp. 60-65 ◽

Cited By ~ 2

Author(s):

Weixuan Wang ◽

Yang Sui ◽

Lulu Zhang ◽

Wei Tan ◽

Xiangwei He ◽

...

Keyword(s):

Small Molecules ◽

Ionization Mass ◽

Binding Affinities ◽

Quadruplex Structure ◽

Novel Approach ◽

G Quadruplex ◽

Before And After ◽

Anti Hiv ◽

Thermal Stability Of ◽

Hiv 1

Targeting a G-quadruplex with chemical small molecules is a useful strategy for gene therapy for disease. The guanine-rich sequence d(5′-TG1G2CCTG3G4G5CG6G7G8ACTG9G10G11-3′) in the HIV-1 promoter can form a G-quadruplex structure. In this study, circular dichroism was performed to study the conformation and thermal stability of the HIV-1 G-quadruplex before and after adding small molecules. A DMS footprinting assay was used to identify which guanosine can be integrated into the G-quadruplex structure. Electrospray ionization mass spectrometry was used to evaluate the binding affinities of the small molecules with the G-quadruplex. Our results showed that G1, G2, G3, G4, G7, G8, G9, and G10 of the above oligonucleotides formed a two G-tetrad antiparallel G-quadrulex, and nitidine chloride was found to have the highest binding affinity toward the HIV-1 G-quadruplex among the eight studied small molecules. The Tm value of the G-quadruplex was enhanced from 56.6 to 63.2 °C when fourfold nitidine chloride was added. This is potentially a novel approach for anti-HIV-1 drug development.

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Faculty Opinions recommendation of A novel approach of water-soluble paclitaxel prodrug with no auxiliary and no byproduct: design and synthesis of isotaxel.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1015189.195954 ◽

2003 ◽

Author(s):

Thomas W von Geldern

Keyword(s):

Water Soluble ◽

Design And Synthesis ◽

Novel Approach

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Responsive and Personalized Web Layouts with Integer Programming

Proceedings of the ACM on Human-Computer Interaction ◽

10.1145/3461735 ◽

2021 ◽

Vol 5 (EICS) ◽

pp. 1-23

Author(s):

Markku Laine ◽

Yu Zhang ◽

Simo Santala ◽

Jussi P. P. Jokinen ◽

Antti Oulasvirta

Keyword(s):

Integer Programming ◽

Web Design ◽

Web Pages ◽

Web Page Design ◽

Automated Generation ◽

Novel Approach ◽

Wide Range ◽

Responsive Design ◽

Responsive Web Design ◽

Page Design

Over the past decade, responsive web design (RWD) has become the de facto standard for adapting web pages to a wide range of devices used for browsing. While RWD has improved the usability of web pages, it is not without drawbacks and limitations: designers and developers must manually design the web layouts for multiple screen sizes and implement associated adaptation rules, and its "one responsive design fits all" approach lacks support for personalization. This paper presents a novel approach for automated generation of responsive and personalized web layouts. Given an existing web page design and preferences related to design objectives, our integer programming -based optimizer generates a consistent set of web designs. Where relevant data is available, these can be further automatically personalized for the user and browsing device. The paper includes presentation of techniques for runtime adaptation of the designs generated into a fully responsive grid layout for web browsing. Results from our ratings-based online studies with end users (N = 86) and designers (N = 64) show that the proposed approach can automatically create high-quality responsive web layouts for a variety of real-world websites.

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Insights into the Antioxidant Mechanism of Newly Synthesized Benzoxazinic Nitrones: In Vitro and In Silico Studies with DPPH Model Radical

Antioxidants ◽

10.3390/antiox10081224 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1224

Author(s):

Stefania Marano ◽

Cristina Minnelli ◽

Lorenzo Ripani ◽

Massimo Marcaccio ◽

Emiliano Laudadio ◽

...

Keyword(s):

Antioxidant Activity ◽

Epr Spectroscopy ◽

Point Of View ◽

Uv Spectrophotometry ◽

Design And Synthesis ◽

Antioxidant Mechanism ◽

Primary Mechanism ◽

In Silico Studies ◽

Wide Range

Synthetic nitrone spin-traps are being explored as therapeutic agents for the treatment of a wide range of oxidative stress-related pathologies, including but not limited to stroke, cancer, cardiovascular, and neurodegenerative diseases. In this context, increasing efforts are currently being made to the design and synthesis of new nitrone-based compounds with enhanced efficacy. The most researched nitrones are surely the ones related to α-phenyl-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) derivatives, which have shown to possess potent biological activity in many experimental animal models. However, more recently, nitrones with a benzoxazinic structure (3-aryl-2H-benzo[1,4]oxazin-N-oxides) have been demonstrated to have superior antioxidant activity compared to PBN. In this study, two new benzoxazinic nitrones bearing an electron-withdrawing methoxycarbonyl group on the benzo moiety (in para and meta positions respect to the nitronyl function) were synthesized. Their in vitro antioxidant activity was evaluated by two cellular-based assays (inhibition of AAPH-induced human erythrocyte hemolysis and cell death in human retinal pigmented epithelium (ARPE-19) cells) and a chemical approach by means of the α,α-diphenyl-β-picrylhydrazyl (DPPH) scavenging assay, using both electron paramagnetic resonance (EPR) spectroscopy and UV spectrophotometry. A computational approach was also used to investigate their potential primary mechanism of antioxidant action, as well as to rationalize the effect of functionalization on the nitrones reactivity toward DPPH, chosen as model radical in this study. Further insights were also gathered by exploring the nitrone electrochemical properties via cyclic voltammetry and by studying their kinetic behavior by means of EPR spectroscopy. Results showed that the introduction of an electron-withdrawing group in the phenyl moiety in the para position significantly increased the antioxidant capacity of benzoxazinic nitrones both in cell and cell-free systems. From the mechanistic point of view, the calculated results closely matched the experimental findings, strongly suggesting that the H-atom transfer (HAT) is likely to be the primary mechanism in the DPPH quenching.

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HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

Virology Journal ◽

10.1186/s12985-021-01514-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Xiaohong Zhou ◽

Christina Monnie ◽

Maria DeLucia ◽

Jinwoo Ahn

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Arrest ◽

Histone Deacetylase ◽

E3 Ligase ◽

Cycle Arrest ◽

Wide Range ◽

In Vitro Reconstitution ◽

Hiv 1

Abstract Background Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4. Because Vpr-mediated degradation of its known targets can not explain the primary cell-cycle arrest phenotype that Vpr expression induces, we surveyed the literature for DNA-repair-associated proteins that interact with the CRL4-DCAF1. One such protein is SIRT7, a deacetylase of histone 3 that belongs to the Sirtuin family and regulates a wide range of cellular processes. We wondered whether Vpr can mediate degradation of SIRT7 via the CRL4-DCAF1. Methods HEK293T cells were transfected with cocktails of plasmids expressing DCAF1, DDB1, SIRT7 and Vpr. Ectopic and endogeneous levels of SIRT7 were monitered by immunoblotting and protein–protein interactions were assessed by immunoprecipitation. For in vitro reconstitution assays, recombinant CRL4-DCAF1-Vpr complexes and SIRT7 were prepared and poly-ubiqutination of SIRT7 was monitored with immunoblotting. Results We demonstrate SIRT7 polyubiquitination and degradation upon Vpr expression. Specifically, SIRT7 is shown to interact with the CRL4-DCAF1 complex, and expression of Vpr in HEK293T cells results in SIRT7 degradation, which is partially rescued by CRL inhibitor MNL4924 and proteasome inhibitor MG132. Further, in vitro reconstitution assays show that Vpr induces poly-ubiquitination of SIRT7 by the CRL4-DCAF1. Importantly, we find that Vpr from several different HIV-1 strains, but not HIV-2 strains, mediates SIRT7 poly-ubiquitination in the reconstitution assay and degradation in cells. Finally, we show that SIRT7 degradation by Vpr is independent of the known, distinctive phenotype of Vpr-induced cell cycle arrest at the G2 phase, Conclusions Targeting histone deacetylase SIRT7 for degradation is a conserved feature of HIV-1 Vpr. Altogether, our findings reveal that HIV-1 Vpr mediates down-regulation of SIRT7 by a mechanism that does not involve novel target recruitment to the CRL4-DCAF1 but instead involves regulation of the E3 ligase activity.

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A Perspective on the Application of Covalent Organic Frameworks for Detection and Water Treatment

Nanomaterials ◽

10.3390/nano11071651 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1651

Author(s):

Cristina Arqueros ◽

Félix Zamora ◽

Carmen Montoro

Keyword(s):

Water Treatment ◽

Resource Scarcity ◽

Covalent Organic Frameworks ◽

Design Strategies ◽

Free Standing ◽

Water And Wastewater Treatment ◽

Design And Synthesis ◽

Water Detection ◽

Wide Range ◽

Quality Water

Global population growth and water resource scarcity are significant social problems currently being studied by many researchers focusing on finding new materials for water treatment. The aim is to obtain quality water suitable for drinking and industrial consumption. In this sense, an emergent class of crystalline porous materials known as Covalent-Organic Frameworks (COFs) offers a wide range of possibilities since their structures can be designed on demand for specific applications. Indeed, in the last decade, many efforts have been made for their use in water treatment. This perspective article aims to overview the state-of-the-art COFs collecting the most recent results in the field for water detection of pollutants and water treatment. After the introduction, where we overview the classical design strategies on COF design and synthesis for obtaining chemically stable COFs, we summarize the different experimental methodologies used for COFs processing in the form of supported and free-standing membranes and colloids. Finally, we describe the use of COFs in processes involving the detection of pollutants in water and wastewater treatment, such as the capture of organic compounds, heavy metals, and dyes, the degradation of organic pollutants, as well as in desalination processes. Finally, we provide a perspective on the field and the potential technological use of these novel materials.

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Density Guarantee on Finding Multiple Subgraphs and Subtensors

ACM Transactions on Knowledge Discovery from Data ◽

10.1145/3446668 ◽

2021 ◽

Vol 15 (5) ◽

pp. 1-32

Author(s):

Quang-huy Duong ◽

Heri Ramampiaro ◽

Kjetil Nørvåg ◽

Thu-lan Dam

Keyword(s):

Lower Bound ◽

State Of The Art ◽

The State ◽

The Other ◽

Exact Methods ◽

Practical Solution ◽

Novel Approach ◽

Wide Range ◽

Real World Datasets ◽

Tensor Data

Dense subregion (subgraph & subtensor) detection is a well-studied area, with a wide range of applications, and numerous efficient approaches and algorithms have been proposed. Approximation approaches are commonly used for detecting dense subregions due to the complexity of the exact methods. Existing algorithms are generally efficient for dense subtensor and subgraph detection, and can perform well in many applications. However, most of the existing works utilize the state-or-the-art greedy 2-approximation algorithm to capably provide solutions with a loose theoretical density guarantee. The main drawback of most of these algorithms is that they can estimate only one subtensor, or subgraph, at a time, with a low guarantee on its density. While some methods can, on the other hand, estimate multiple subtensors, they can give a guarantee on the density with respect to the input tensor for the first estimated subsensor only. We address these drawbacks by providing both theoretical and practical solution for estimating multiple dense subtensors in tensor data and giving a higher lower bound of the density. In particular, we guarantee and prove a higher bound of the lower-bound density of the estimated subgraph and subtensors. We also propose a novel approach to show that there are multiple dense subtensors with a guarantee on its density that is greater than the lower bound used in the state-of-the-art algorithms. We evaluate our approach with extensive experiments on several real-world datasets, which demonstrates its efficiency and feasibility.

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