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Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications

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Special Issue Information
Keywords
Published Papers

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 18598

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Special Issue Editors

Dr. Claudia Riccardi

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Guest Editor

Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
Interests: ruthenium complexes; platinum complexes; benzodifuran compounds; oligonucleotides; G-quadruplex; aptamers; thrombin binding aptamers; nanosystems; nanomaterials
Special Issues, Collections and Topics in MDPI journals

Dr. Domenica Musumeci

E-Mail Website
Guest Editor

Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
Interests: oligonucleotide aptamers; oligonucleotide analogs; nucleopeptides; metal-based drugs; DNA-small molecule interaction; DNA-protein interaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oligonucleotides, peptides, and their analogues have attracted a growing amount of interest in biomedicine due to their potential value for both therapeutic and diagnostic applications in different diseases.

The efficacy of these molecules is mainly based on the specific recognition of different key targets, from small species (metal ions, metabolites) to large proteins with an important role in various physiological or pathological conditions.

Furthermore, oligonucleotides, and peptides can be ad hoc modified, conjugated to specific markers, or used to decorate multifunctional systems in order to improve their effectiveness in terms of chemical or enzymatic stability, delivery, and cellular uptake (if cell entrance is required).

We would like to cordially invite all scientists engaged in this research field to contribute to the success of this Special Issue aiming at emphasizing the wonderful world surrounding oligonucleotides and peptides in their multiple applications.

This Special Issue of Molecules will include both regular articles and reviews focused on the most recent advances in the field of the molecular recognition of key targets by oligonucleotides, peptides, and their analogues. Contributions dealing with oligonucleotide/peptide chemical modifications and structural characterization, structure–activity relationships, mechanism of action, target identification, interactions with the target, and so on are particularly welcome.

Dr. Claudia Riccardi
Dr. Domenica Musumeci
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Oligonucleotides and analogues
Peptides and peptidomimetics
Chemical modifications
Structural characterization
Structure–activity relationship
Molecular recognition
Binding partners (e.g., ions, metabolites, proteins)
Biophysical/biochemical investigations
Conjugation strategies
Therapeutic/diagnostic applications

Published Papers (6 papers)

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Research

Jump to: Review

13 pages, 2022 KiB

Open AccessArticle

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

by Wassim Moslah, Dorra Aissaoui-Zid, Soioulata Aboudou, Zaineb Abdelkafi-Koubaa, Marie Potier-Cartereau, Aude Lemettre, Ines ELBini-Dhouib, Naziha Marrakchi, Didier Gigmes, Christophe Vandier, José Luis, Kamel Mabrouk and Najet Srairi-Abid

Molecules 2022, 27(3), 806; https://doi.org/10.3390/molecules27030806 - 26 Jan 2022

Cited by 7 | Viewed by 2399

Abstract

Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC₅₀ value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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17 pages, 3095 KiB

Open AccessArticle

Stability Enhancement of a Dimeric HER2-Specific Affibody Molecule through Sortase A-Catalyzed Head-to-Tail Cyclization

by Kristina Westerlund, Anders Myrhammar, Hanna Tano, Maxime Gestin and Amelie Eriksson Karlström

Molecules 2021, 26(10), 2874; https://doi.org/10.3390/molecules26102874 - 12 May 2021

Cited by 5 | Viewed by 2415

Abstract

Natural backbone-cyclized proteins have an increased thermostability and resistance towards proteases, characteristics that have sparked interest in head-to-tail cyclization as a method to stability-enhance proteins used in diagnostics and therapeutic applications, for example. In this proof-of principle study, we have produced and investigated a head-to-tail cyclized and HER2-specific Z_HER2:342 Affibody dimer. The sortase A-mediated cyclization reaction is highly efficient (>95%) under optimized conditions, and renders a cyclic Z_HER3:342-dimer with an apparent melting temperature, T_m, of 68 °C, which is 3 °C higher than that of its linear counterpart. Circular dichroism spectra of the linear and cyclic dimers looked very similar in the far-UV range, both before and after thermal unfolding to 90 °C, which suggests that cyclization does not negatively impact the helicity or folding of the cyclic protein. The cyclic dimer had an apparent sub-nanomolar affinity (K_d ~750 pM) to the HER2-receptor, which is a ~150-fold reduction in affinity relative to the linear dimer (K_d ~5 pM), but the anti-HER2 Affibody dimer remained a high-affinity binder even after cyclization. No apparent difference in proteolytic stability was detected in an endopeptidase degradation assay for the cyclic and linear dimers. In contrast, in an exopeptidase degradation assay, the linear dimer was shown to be completely degraded after 5 min, while the cyclic dimer showed no detectable degradation even after 60 min. We further demonstrate that a site-specifically DyLight 594-labeled cyclic dimer shows specific binding to HER2-overexpressing cells. Taken together, the results presented here demonstrate that head-to-tail cyclization can be an effective strategy to increase the stability of an Affibody dimer. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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14 pages, 2935 KiB

Open AccessArticle

Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2′-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells

by Anna Clua, Carme Fàbrega, Jesús García-Chica, Santiago Grijalvo and Ramon Eritja

Molecules 2021, 26(6), 1741; https://doi.org/10.3390/molecules26061741 - 20 Mar 2021

Cited by 5 | Viewed by 2680

Abstract

Fluoropyrimidines, such as 5-fluorouracil (5-FU) and related prodrugs have been considered first-line chemotherapy agents for the treatment of colorectal cancer. However, poor specificity and tumor cell resistance remain major limiting bottlenecks. G-quadruplexes, have been suggested as preferred nanostructures for enhancing cellular uptake mediated by G-quadruplex binding proteins which are abundant at the membranes of some tumor cells. In the current study, we propose a new strategy to deliver 5-fluoro-2′-deoxyuridine (5-FdU) monophosphate, the main active drug from 5-FU derivatives that may circumvent the cellular mechanisms of FU-resistant cancer cells. Two G-quadruplexes delivery systems containing four and six G-tetrads ((TG₄T) and (TG₆T)) linked to a FdU oligonucleotide were synthesized. Biophysical studies show that the G-quadruplex parallel structures are not affected by the incorporation of the 5 units of FdU at the 5’-end. Internalization studies confirmed the ability of such G-quadruplex nanostructures to facilitate the transport of the FdU pentamer and increase its cytotoxic effect relative to conventional FU drug in FU-resistant colorectal cancer cells. These results suggest that FdU oligomers linked to G-quadruplex parallel sequences may be a promising strategy to deliver fluoropyrimidines to cancer cells. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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Review

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16 pages, 1989 KiB

Open AccessReview

Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases

by Luis H. Gutiérrez-González, Selma Rivas-Fuentes, Silvia Guzmán-Beltrán, Angélica Flores-Flores, Jorge Rosas-García and Teresa Santos-Mendoza

Molecules 2021, 26(21), 6367; https://doi.org/10.3390/molecules26216367 - 21 Oct 2021

Cited by 2 | Viewed by 2636

Abstract

PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein–protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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16 pages, 3667 KiB

Open AccessReview

From Prebiotic Chemistry to Supramolecular Biomedical Materials: Exploring the Properties of Self-Assembling Nucleobase-Containing Peptides

by Pasqualina Liana Scognamiglio, Chiara Platella, Ettore Napolitano, Domenica Musumeci and Giovanni Nicola Roviello

Molecules 2021, 26(12), 3558; https://doi.org/10.3390/molecules26123558 - 10 Jun 2021

Cited by 18 | Viewed by 3296

Abstract

Peptides and their synthetic analogs are a class of molecules with enormous relevance as therapeutics for their ability to interact with biomacromolecules like nucleic acids and proteins, potentially interfering with biological pathways often involved in the onset and progression of pathologies of high social impact. Nucleobase-bearing peptides (nucleopeptides) and pseudopeptides (PNAs) offer further interesting possibilities related to their nucleobase-decorated nature for diagnostic and therapeutic applications, thanks to their reported ability to target complementary DNA and RNA strands. In addition, these chimeric compounds are endowed with intriguing self-assembling properties, which are at the heart of their investigation as self-replicating materials in prebiotic chemistry, as well as their application as constituents of innovative drug delivery systems and, more generally, as novel nanomaterials to be employed in biomedicine. Herein we describe the properties of nucleopeptides, PNAs and related supramolecular systems, and summarize some of the most relevant applications of these systems. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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34 pages, 2975 KiB

Open AccessReview

Dimeric and Multimeric DNA Aptamers for Highly Effective Protein Recognition

by Claudia Riccardi, Ettore Napolitano, Domenica Musumeci and Daniela Montesarchio

Molecules 2020, 25(22), 5227; https://doi.org/10.3390/molecules25225227 - 10 Nov 2020

Cited by 25 | Viewed by 4438

Abstract

Multivalent interactions frequently occur in biological systems and typically provide higher binding affinity and selectivity in target recognition than when only monovalent interactions are operative. Thus, taking inspiration by nature, bivalent or multivalent nucleic acid aptamers recognizing a specific biological target have been extensively studied in the last decades. Indeed, oligonucleotide-based aptamers are suitable building blocks for the development of highly efficient multivalent systems since they can be easily modified and assembled exploiting proper connecting linkers of different nature. Thus, substantial research efforts have been put in the construction of dimeric/multimeric versions of effective aptamers with various degrees of success in target binding affinity or therapeutic activity enhancement. The present review summarizes recent advances in the design and development of dimeric and multimeric DNA-based aptamers, including those forming G-quadruplex (G4) structures, recognizing different key proteins in relevant pathological processes. Most of the designed constructs have shown improved performance in terms of binding affinity or therapeutic activity as anti-inflammatory, antiviral, anticoagulant, and anticancer agents and their number is certainly bound to grow in the next future. Full article

(This article belongs to the Special Issue Oligonucleotides, Peptides, and Their Analogues in Key Target Recognition for Therapeutic and Diagnostic Applications)

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