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18 pages, 3211 KiB

Open AccessArticle

Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids

by Stephen Neidle

Pharmaceuticals 2022, 15(1), 7; https://doi.org/10.3390/ph15010007 - 22 Dec 2021

Cited by 25 | Viewed by 4531

Abstract

The role of G-quadruplexes in human cancers is increasingly well-defined. Accordingly, G-quadruplexes can be suitable drug targets and many small molecules have been identified to date as G-quadruplex binders, some using computer-based design methods and co-crystal structures. The role of bound water molecules [...] Read more.

The role of G-quadruplexes in human cancers is increasingly well-defined. Accordingly, G-quadruplexes can be suitable drug targets and many small molecules have been identified to date as G-quadruplex binders, some using computer-based design methods and co-crystal structures. The role of bound water molecules in the crystal structures of G-quadruplex-small molecule complexes has been analyzed in this study, focusing on the water arrangements in several G-quadruplex ligand complexes. One is the complex between the tetrasubstituted naphthalene diimide compound MM41 and a human intramolecular telomeric DNA G-quadruplex, and the others are in substituted acridine bimolecular G-quadruplex complexes. Bridging water molecules form most of the hydrogen-bond contacts between ligands and DNA in the parallel G-quadruplex structures examined here. Clusters of structured water molecules play essential roles in mediating between ligand side chain groups/chromophore core and G-quadruplex. These clusters tend to be conserved between complex and native G-quadruplex structures, suggesting that they more generally serve as platforms for ligand binding, and should be taken into account in docking and in silico studies. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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22 pages, 3376 KiB

Open AccessArticle

New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study

by Enrico Cadoni, Pedro R. Magalhães, Rita M. Emídio, Eduarda Mendes, Jorge Vítor, Josué Carvalho, Carla Cruz, Bruno L. Victor and Alexandra Paulo

Pharmaceuticals 2021, 14(7), 669; https://doi.org/10.3390/ph14070669 - 13 Jul 2021

Cited by 11 | Viewed by 3773

Abstract

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure–activity relationships [...] Read more.

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure–activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds’ ability to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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20 pages, 5542 KiB

Open AccessArticle

Locking up the AS1411 Aptamer with a Flanking Duplex: Towards an Improved Nucleolin-Targeting

by André Miranda, Tiago Santos, Eric Largy and Carla Cruz

Pharmaceuticals 2021, 14(2), 121; https://doi.org/10.3390/ph14020121 - 4 Feb 2021

Cited by 21 | Viewed by 4878

Abstract

We have designed AS1411-N6, a derivative of the nucleolin (NCL)-binding aptamer AS1411, by adding six nucleotides to the 5′-end that are complementary to nucleotides at the 3′-end forcing it into a stem-loop structure. We evaluated by several biophysical techniques if AS1411-N6 can adopt [...] Read more.

We have designed AS1411-N6, a derivative of the nucleolin (NCL)-binding aptamer AS1411, by adding six nucleotides to the 5′-end that are complementary to nucleotides at the 3′-end forcing it into a stem-loop structure. We evaluated by several biophysical techniques if AS1411-N6 can adopt one or more conformations, one of which allows NCL binding. We found a decrease of polymorphism of G-quadruplex (G4)-forming sequences comparing to AS1411 and the G4 formation in presence of K⁺ promotes the duplex folding. We also studied the binding properties of ligands TMPyP4, PhenDC3, PDS, 360A, and BRACO-19 in terms of stability, binding, topology maintenance of AS1411-N6, and NCL recognition. The melting experiments revealed promising stabilizer effects of PhenDC3, 360A, and TMPyP4, and the affinity calculations showed that 360A is the most prominent affinity ligand for AS1411-N6 and AS1411. The affinity determined between AS1411-N6 and NCL denoting a strong interaction and complex formation was assessed by PAGE in which the electrophoretic profile of AS1411-N6 showed bands of the dimeric form in the presence of the ligands and NCL. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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Review

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58 pages, 34211 KiB

Open AccessReview

Major Achievements in the Design of Quadruplex-Interactive Small Molecules

by Eduarda Mendes, Israa M. Aljnadi, Bárbara Bahls, Bruno L. Victor and Alexandra Paulo

Pharmaceuticals 2022, 15(3), 300; https://doi.org/10.3390/ph15030300 - 28 Feb 2022

Cited by 34 | Viewed by 5710

Abstract

Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules [...] Read more.

Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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40 pages, 8823 KiB

Open AccessEditor’s ChoiceReview

G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions

by Tiago Santos, Gilmar F. Salgado, Eurico J. Cabrita and Carla Cruz

Pharmaceuticals 2021, 14(8), 769; https://doi.org/10.3390/ph14080769 - 5 Aug 2021

Cited by 80 | Viewed by 11206

Abstract

Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be [...] Read more.

Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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28 pages, 2869 KiB

Open AccessFeature PaperReview

G-Quadruplex-Based Drug Delivery Systems for Cancer Therapy

by Jéssica Lopes-Nunes, Paula A. Oliveira and Carla Cruz

Pharmaceuticals 2021, 14(7), 671; https://doi.org/10.3390/ph14070671 - 13 Jul 2021

Cited by 25 | Viewed by 5173

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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41 pages, 15723 KiB

Open AccessReview

Metal-Based G-Quadruplex Binders for Cancer Theranostics

by Elisa Palma, Josué Carvalho, Carla Cruz and António Paulo

Pharmaceuticals 2021, 14(7), 605; https://doi.org/10.3390/ph14070605 - 23 Jun 2021

Cited by 30 | Viewed by 5354

Abstract

The ability of fluorescent small molecules, such as metal complexes, to selectively recognize G-quadruplex (G4) structures has opened a route to develop new probes for the visualization of these DNA structures in cells. The main goal of this review is to update the [...] Read more.

The ability of fluorescent small molecules, such as metal complexes, to selectively recognize G-quadruplex (G4) structures has opened a route to develop new probes for the visualization of these DNA structures in cells. The main goal of this review is to update the most recent research efforts towards the development of novel cancer theranostic agents using this type of metal-based probes that specifically recognize G4 structures. This encompassed a comprehensive overview of the most significant progress in the field, namely based on complexes with Cu, Pt, and Ru that are among the most studied metals to obtain this class of molecules. It is also discussed the potential interest of obtaining G4-binders with medical radiometals (e.g., ^99mTc, ¹¹¹In, ⁶⁴Cu, ^195mPt) suitable for diagnostic and/or therapeutic applications within nuclear medicine modalities, in order to enable their theranostic potential. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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24 pages, 2068 KiB

Open AccessReview

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

by Susie L. Brown and Samantha Kendrick

Pharmaceuticals 2021, 14(2), 96; https://doi.org/10.3390/ph14020096 - 27 Jan 2021

Cited by 54 | Viewed by 9579

Abstract

Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences [...] Read more.

Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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Other

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13 pages, 1810 KiB

Open AccessPerspective

Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future Anticancer Therapeutic Applications

by Riccardo Rigo, Elisabetta Groaz and Claudia Sissi

Pharmaceuticals 2022, 15(3), 373; https://doi.org/10.3390/ph15030373 - 19 Mar 2022

Cited by 8 | Viewed by 3106

Abstract

In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they [...] Read more.

In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they can fold into non-canonical tetrahelical structures known as G-quadruplexes. However, emerging evidence points to a frequent lack of correlation between small molecule targeting of G-quadruplexes at gene promoters and the expression of the associated protein, which hampers pharmaceutical applications. The wide genomic localization of G-quadruplexes along with their highly polymorphic behavior may account for this scenario, suggesting the need for more focused drug design strategies. Here, we will summarize the G4 structural features that can be considered to fulfill this goal. In particular, by comparing a telomeric sequence with the well-characterized G-rich domain of the KIT promoter, we will address how multiple secondary structures might cooperate to control genome architecture at a higher level. If this holds true, the link between drug–DNA complex formation and the associated cellular effects will need to be revisited. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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