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Pharmaceuticals
Special Issues
Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs
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Special Issue "Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 December 2023 | Viewed by 5997

Special Issue Editor

Prof. Dr. Deirdre R. Coombe

E-Mail Website
Guest Editor
Curtin Medical School, Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia
Interests: heparin mimetics; drug discovery; respiratory inflammatory disease; heparanase; SARS-CoV-2; glycosaminoglycan; extracellular matrix

Special Issue Information

Dear Colleagues,

In the last couple of years, there has been a resurgence of interest in heparin and related drugs. In part, this was fueled by the COVID-19 pandemic and the revelation that heparin and heparan sulfate can interact with the SARS-CoV-2 spike protein and inhibit SARS-CoV-2 infection in vitro. These findings came on the back of a greater appreciation that heparin has a wide range of activities that are not related to anti-coagulation, with its anti-inflammatory, anti-viral, and anti-cancer effects being particularly well known.

Until recently, capitalizing on heparin’s non-anticoagulant activities for the development of new drugs has been difficult because of limitations in technologies for the synthesis and structural analysis of these complex polysaccharides. However, years of work have led to methodologies that enable the performance of detailed structural analyses of natural heparin and heparan sulfate fragments, and of synthetic heparin mimetics. Coupled with this, better molecular modelling methodologies for understanding the structure–function interactions of both the natural fragments and the mimetics are under development. The adaptation of organic chemistry synthesis techniques to the production of heparin mimetics and the chemoenzymatic syntheses of heparin and heparin-like fragments means the stage is now set for an exploration of the chemical space occupied by these structures and their potential as drugs.

This Special Issue aims to highlight the excitement felt by many of us in this field at these developments. The journal Pharmaceuticals invites both reviews and original articles on the challenges and opportunities of developing heparin and heparin-inspired molecules for drugs targeting disease indications with inflammatory, viral or cancerous components. The collection of manuscripts will be published as a Special Issue entitled “Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs”.

Prof. Dr. Deirdre R. Coombe
Guest Editor

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • heparin
  • heparan sulfate mimic
  • heparin mimetic
  • heparin-like
  • heparinoids
  • sulfated polysaccharide drug
  • heparosan

Published Papers (5 papers)

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Research

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15 pages, 1919 KiB  
Article
Extraction, Isolation, Characterization, and Biological Activity of Sulfated Polysaccharides Present in Ascidian Viscera Microcosmus exasperatus
by
Ananda de Araujo Bento
,
Marianna Cardoso Maciel
,
Francisco Felipe Bezerra
,
Paulo Antônio de Souza Mourão
,
Mauro Sérgio Gonçalves Pavão
and
Mariana Paranhos Stelling
Pharmaceuticals 2023, 16(10), 1401; https://doi.org/10.3390/ph16101401 - 03 Oct 2023
Viewed by 589
Abstract
Ascidians are marine invertebrates that synthesize sulfated glycosaminoglycans (GAGs) within their viscera. Ascidian GAGs are considered analogues of mammalian GAGs and possess great potential as bioactive compounds, presenting antitumoral and anticoagulant activity. Due to its worldwide occurrence and, therefore, being a suitable organism [...] Read more.
Ascidians are marine invertebrates that synthesize sulfated glycosaminoglycans (GAGs) within their viscera. Ascidian GAGs are considered analogues of mammalian GAGs and possess great potential as bioactive compounds, presenting antitumoral and anticoagulant activity. Due to its worldwide occurrence and, therefore, being a suitable organism for large-scale mariculture in many marine environments, our main objectives are to study Microcosmus exasperatus GAGs regarding composition, structure, and biological activity. We also aim to develop efficient protocols for sulfated polysaccharides extraction and purification for large-scale production and clinical applications. GAGs derived from M. exasperatus viscera were extracted by proteolytic digestion, purified by ion-exchange liquid chromatography, and characterized by agarose gel electrophoresis and enzymatic treatments. Anticoagulant activity was evaluated by APTT assays. Antitumoral activity was assessed in an in vitro model of tumor cell culture using MTT, clonogenic, and wound healing assays, respectively. Our results show that M. exasperatus presents three distinct polysaccharides; among them, two were identified: a dermatan sulfate and a fucosylated dermatan sulfate. Antitumoral activity was confirmed for the total polysaccharides (TP). While short-term incubation does not affect tumor cell viability at low concentrations, long-term TP incubation decreases LLC tumor cell growth/proliferation at different concentrations. In addition, TP decreased tumor cell migration at different concentrations. In conclusion, we state that M. exasperatus presents great potential as an alternative GAG source, producing compounds with antitumoral properties at low concentrations that do not possess anticoagulant activity and do not enhance other aspects of malignancy, such as tumor cell migration. Our perspectives are to apply these molecules in future preclinical studies for cancer treatment as antitumoral agents to be combined with current treatments to potentiate therapeutic efficacy. Full article
(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)
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17 pages, 1222 KiB  
Article
Heparin Precursors with Reduced Anticoagulant Properties Retain Antiviral and Protective Effects That Potentiate the Efficacy of Sofosbuvir against Zika Virus Infection in Human Neural Progenitor Cells
by
Isabel Pagani
,
Linda Ottoboni
,
Paola Panina-Bordignon
,
Gianvito Martino
,
Guido Poli
,
Sarah Taylor
,
Jeremy E. Turnbull
,
Edwin Yates
and
Elisa Vicenzi
Pharmaceuticals 2023, 16(10), 1385; https://doi.org/10.3390/ph16101385 - 29 Sep 2023
Viewed by 484
Abstract
Zika virus (ZIKV) infection during pregnancy can result in severe birth defects, such as microcephaly, as well as a range of other related health complications. Heparin, a clinical-grade anticoagulant, is shown to protect neural progenitor cells from death following ZIKV infection. Although heparin [...] Read more.
Zika virus (ZIKV) infection during pregnancy can result in severe birth defects, such as microcephaly, as well as a range of other related health complications. Heparin, a clinical-grade anticoagulant, is shown to protect neural progenitor cells from death following ZIKV infection. Although heparin can be safely used during pregnancy, it retains off-target anticoagulant effects if directly employed against ZIKV infection. In this study, we investigated the effects of chemically modified heparin derivatives with reduced anticoagulant activities. These derivatives were used as experimental probes to explore the structure–activity relationships. Precursor fractions of porcine heparin, obtained during the manufacture of conventional pharmaceutical heparin with decreased anticoagulant activities, were also explored. Interestingly, these modified heparin derivatives and precursor fractions not only prevented cell death but also inhibited the ZIKV replication of infected neural progenitor cells grown as neurospheres. These effects were observed regardless of the specific sulfation position or overall charge. Furthermore, the combination of heparin with Sofosbuvir, an antiviral licensed for the treatment of hepatitis C (HCV) that also belongs to the same Flaviviridae family as ZIKV, showed a synergistic effect. This suggested that a combination therapy approach involving heparin precursors and Sofosbuvir could be a potential strategy for the prevention or treatment of ZIKV infections. Full article
(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)
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Review

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26 pages, 1363 KiB  
Review
Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease
by
Janis Kay Shute
Pharmaceuticals 2023, 16(4), 584; https://doi.org/10.3390/ph16040584 - 13 Apr 2023
Cited by 3 | Viewed by 1864
Abstract
Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion [...] Read more.
Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route. Full article
(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)
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18 pages, 685 KiB  
Review
Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment
by
John Hogwood
,
Elaine Gray
and
Barbara Mulloy
Pharmaceuticals 2023, 16(2), 271; https://doi.org/10.3390/ph16020271 - 10 Feb 2023
Cited by 1 | Viewed by 1382
Abstract
Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms [...] Read more.
Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis. Full article
(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)
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Other

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9 pages, 1112 KiB  
Opinion
Heparin Mimetics and Their Impact on Extracellular Matrix Protein Assemblies
by
Fabian Heide
,
Manuel Koch
and
Jörg Stetefeld
Pharmaceuticals 2023, 16(3), 471; https://doi.org/10.3390/ph16030471 - 22 Mar 2023
Viewed by 1088
Abstract
Heparan sulfate is a crucial extracellular matrix component that organizes structural features and functional protein processes. This occurs through the formation of protein–heparan sulfate assemblies around cell surfaces, which allow for the deliberate local and temporal control of cellular signaling. As such, heparin-mimicking [...] Read more.
Heparan sulfate is a crucial extracellular matrix component that organizes structural features and functional protein processes. This occurs through the formation of protein–heparan sulfate assemblies around cell surfaces, which allow for the deliberate local and temporal control of cellular signaling. As such, heparin-mimicking drugs can directly affect these processes by competing with naturally occurring heparan sulfate and heparin chains that then disturb protein assemblies and decrease regulatory capacities. The high number of heparan-sulfate-binding proteins that are present in the extracellular matrix can cause obscure pathological effects that should be considered and examined in more detail, especially when developing novel mimetics for clinical use. The objective of this article is to investigate recent studies that present heparan-sulfate-mediated protein assemblies and the impact of heparin mimetics on the assembly and function of these protein complexes. Full article
(This article belongs to the Special Issue Medicinal Chemistry and Pharmacological Activities of Heparin and Related Drugs)
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