Editorial

4 pages, 202 KiB

Open AccessEditorial

Glycomimetics and Glycoconjugates in Drug Discovery

by Nuno M. Xavier and Peter R. Andreana

Pharmaceuticals 2024, 17(3), 323; https://doi.org/10.3390/ph17030323 - 01 Mar 2024

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This Special Issue of Pharmaceuticals presents one review and six original articles that are demonstrative of the importance of glycomimetics and glycoconjugates as privileged groups of carbohydrate-based molecules in the search for and development of bioactive substances for therapeutic/pharmaceutical purposes [...] Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

Research

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27 pages, 7154 KiB

Open AccessArticle

Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors

by Ádám Sipos, Eszter Szennyes, Nikolett Éva Hajnal, Sándor Kun, Katalin E. Szabó, Karen Uray, László Somsák, Tibor Docsa and Éva Bokor

Pharmaceuticals 2021, 14(4), 364; https://doi.org/10.3390/ph14040364 - 15 Apr 2021

Cited by 8 | Viewed by 3413

Abstract

A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) [...] Read more.

A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a K_i of 31 nM for GP and IC₅₀ of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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13 pages, 2316 KiB

Open AccessFeature PaperArticle

Sugar Matters: Improving In Vivo Clearance Rate of Highly Glycosylated Recombinant Plasma Proteins for Therapeutic Use

by Sacha Zeerleder, Ruchira Engel, Tao Zhang, Dorina Roem, Gerard van Mierlo, Ineke Wagenaar-Bos, Sija Marieke van Ham, Manfred Wuhrer, Diana Wouters and Ilse Jongerius

Pharmaceuticals 2021, 14(1), 54; https://doi.org/10.3390/ph14010054 - 11 Jan 2021

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Abstract

Correct glycosylation of proteins is essential for production of therapeutic proteins as glycosylation is important for protein solubility, stability, half-life and immunogenicity. The heavily glycosylated plasma protein C1-inhibitor (C1-INH) is used in treatment of hereditary angioedema attacks. In this study, we used C1-INH [...] Read more.

Correct glycosylation of proteins is essential for production of therapeutic proteins as glycosylation is important for protein solubility, stability, half-life and immunogenicity. The heavily glycosylated plasma protein C1-inhibitor (C1-INH) is used in treatment of hereditary angioedema attacks. In this study, we used C1-INH as a model protein to propose an approach to develop recombinant glycoproteins with the desired glycosylation. We produced fully functional recombinant C1-INH in Chinese hamster ovary (CHO) cells. In vivo we observed a biphasic clearance, indicating different glycosylation forms. N-glycan analysis with mass spectrometry indeed demonstrated heterogeneous glycosylation for recombinant C1-INH containing terminal galactose and terminal sialic acid. Using a Ricinus Communis Agglutinin I (RCA₁₂₀) column, we could reduce the relative abundance of terminal galactose and increase the relative abundance of terminal sialic acid. This resulted in a fully active protein with a similar in vivo clearance rate to plasmaderived C1-INH. In summary, we describe the development of a recombinant human glycoprotein using simple screening tools to obtain a product that is similar in function and in vivo clearance rate to its plasma-derived counterpart. The approach used here is of potential use in the development of other therapeutic recombinant human glycoproteins. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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16 pages, 3819 KiB

Open AccessArticle

Overcoming Hypoxia-Induced Chemoresistance in Cancer Using a Novel Glycoconjugate of Methotrexate

by Marta Woźniak, Gabriela Pastuch-Gawołek, Sebastian Makuch, Jerzy Wiśniewski, Piotr Ziółkowski, Wiesław Szeja, Monika Krawczyk and Siddarth Agrawal

Pharmaceuticals 2021, 14(1), 13; https://doi.org/10.3390/ph14010013 - 24 Dec 2020

Cited by 6 | Viewed by 2770

Abstract

The oxygen and nutrient-deprived tumor microenvironment is considered a key mechanism responsible for cancer resistance to chemotherapy. Methotrexate (MTX) is a widely incorporated chemotherapeutic agent employed in the treatment of several malignancies. However, drug resistance and systemic toxicity limit the curative effect in [...] Read more.

The oxygen and nutrient-deprived tumor microenvironment is considered a key mechanism responsible for cancer resistance to chemotherapy. Methotrexate (MTX) is a widely incorporated chemotherapeutic agent employed in the treatment of several malignancies. However, drug resistance and systemic toxicity limit the curative effect in most cases. The present work aimed to design, synthesize, and biologically evaluate a novel glucose-methotrexate conjugate (Glu-MTX). Our study showed that Glu-MTX exerts an increased cytotoxic effect on cancer cells in comparison to MTX in hypoxia (1% O₂) and glucose starvation conditions. Furthermore, Glu-MTX was found to inhibit the proliferation and migration of cancer cells more effectively than MTX does. Our results demonstrate that the conjugation of MTX to glucose led to an increase in potency against malignant cells under oxygen and nutrient stress. The observations shed light on a potential therapeutic approach to overcome chemoresistance in cancer. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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20 pages, 3222 KiB

Open AccessArticle

Anti-Tick-Borne Encephalitis Virus Activity of Novel Uridine Glycoconjugates Containing Amide or/and 1,2,3-Triazole Moiety in the Linker Structure

by Gabriela Brzuska, Gabriela Pastuch-Gawolek, Monika Krawczyk, Boguslaw Szewczyk and Ewelina Krol

Pharmaceuticals 2020, 13(12), 460; https://doi.org/10.3390/ph13120460 - 13 Dec 2020

Cited by 5 | Viewed by 2359

Abstract

Tick-borne encephalitis virus (TBEV) transmitted by ticks is a pathogen of great medical importance. As still no effective antiviral treatment is available, in the present study, a series of uridine glycoconjugates containing amide or/and 1,2,3-triazole moiety in the linker structure was synthesized and [...] Read more.

Tick-borne encephalitis virus (TBEV) transmitted by ticks is a pathogen of great medical importance. As still no effective antiviral treatment is available, in the present study, a series of uridine glycoconjugates containing amide or/and 1,2,3-triazole moiety in the linker structure was synthesized and evaluated for the antiviral activity against two strains of TBEV: a highly virulent Hypr strain and less virulent Neudoerfl strain, using standardized previously in vitro assays. Our data have shown that four compounds from the series (18–21) possess strong activity against both TBEV strains. The half maximal inhibitory concentration (IC₅₀) values of compounds 18–21 were between 15.1 and 3.7 μM depending on the virus strain, which along with low cytotoxicity resulted in high values of the selectivity index (SI). The obtained results suggest that these compounds may be promising candidates for further development of new therapies against flaviviruses. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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20 pages, 2767 KiB

Open AccessArticle

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

by Jérémy P. Schneider, Stefano Tommasone, Paolo Della Sala, Carmine Gaeta, Carmen Talotta, Céline Tarnus, Placido Neri, Anne Bodlenner and Philippe Compain

Pharmaceuticals 2020, 13(11), 366; https://doi.org/10.3390/ph13110366 - 05 Nov 2020

Cited by 8 | Viewed by 2936

Abstract

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their [...] Read more.

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ K_i being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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18 pages, 2315 KiB

Open AccessArticle

The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations

by J. Daniel Martínez, Angela S. Infantino, Pablo Valverde, Tammo Diercks, Sandra Delgado, Niels-Christian Reichardt, Ana Ardá, Francisco Javier Cañada, Stefan Oscarson and Jesús Jiménez-Barbero

Pharmaceuticals 2020, 13(8), 179; https://doi.org/10.3390/ph13080179 - 04 Aug 2020

Cited by 10 | Viewed by 3871

Abstract

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein–ligand complexes. We herein present a new methodology based [...] Read more.

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein–ligand complexes. We herein present a new methodology based on the synergic combination of experimental ¹⁹F-based saturation transfer difference (STD) NMR data with computational protocols, applied to analyze the interaction between DC-SIGN, a key lectin involved in inflammation and infection events with the trifluorinated glycomimetic of the trimannoside core, ubiquitous in human glycoproteins. A novel 2D-STD-TOCSYreF NMR experiment was employed to obtain the experimental STD NMR intensities, while the Complete Relaxation Matrix Analysis (CORCEMA-ST) was used to predict that expected for an ensemble of geometries extracted from extensive MD simulations. Then, an in-house built computer program was devised to find the ensemble of structures that provide the best fit between the theoretical and the observed STD data. Remarkably, the experimental STD profiles obtained for the ligand/DC-SIGN complex could not be satisfactorily explained by a single binding mode, but rather with a combination of different modes coexisting in solution. Therefore, the method provides a precise view of those ligand–receptor complexes present in solution. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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Review

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27 pages, 4122 KiB

Open AccessReview

Assembly of Peptidoglycan Fragments—A Synthetic Challenge

by Fausto Queda, Gonçalo Covas, Sérgio R. Filipe and M. Manuel B. Marques

Pharmaceuticals 2020, 13(11), 392; https://doi.org/10.3390/ph13110392 - 15 Nov 2020

Cited by 2 | Viewed by 3365

Abstract

Peptidoglycan (PGN) is a major constituent of most bacterial cell walls that is recognized as a primary target of the innate immune system. The availability of pure PGN molecules has become key to different biological studies. This review aims to (1) provide an [...] Read more.

Peptidoglycan (PGN) is a major constituent of most bacterial cell walls that is recognized as a primary target of the innate immune system. The availability of pure PGN molecules has become key to different biological studies. This review aims to (1) provide an overview of PGN biosynthesis, focusing on the main biosynthetic intermediates; (2) focus on the challenges for chemical synthesis posed by the unique and complex structure of PGN; and (3) cover the synthetic routes of PGN fragments developed to date. The key difficulties in the synthesis of PGN molecules mainly involve stereoselective glycosylation involving NAG derivatives. The complex synthesis of the carbohydrate backbone commonly involves multistep sequences of chemical reactions to install the lactyl moiety at the O-3 position of NAG derivatives and to control enantioselective glycosylation. Recent advances are presented and synthetic routes are described according to the main strategy used: (i) based on the availability of starting materials such as glucosamine derivatives; (ii) based on a particular orthogonal synthesis; and (iii) based on the use of other natural biopolymers as raw materials. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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