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Article ; Online: The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

Paiardi, Giulia / Ferraz, Matheus / Rusnati, Marco / Wade, Rebecca C.

bioRxiv

Abstract: The SARS-CoV-2 spike glycoprotein mediates virus attachment to human host cells by binding angiotensin-converting enzyme 2 (ACE2) and heparan sulfate (HS) proteoglycans. To elucidate the structure, dynamics, and functional consequences of these ... ...

Abstract	The SARS-CoV-2 spike glycoprotein mediates virus attachment to human host cells by binding angiotensin-converting enzyme 2 (ACE2) and heparan sulfate (HS) proteoglycans. To elucidate the structure, dynamics, and functional consequences of these interactions, we carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration molecular dynamics simulations, of the fully glycosylated spike:ACE2 complex with and without heparin chains bound. We find that heparin, a model for HS, promotes structural and energetic stabilization of the active conformation of the spike receptor binding domain (RBD) and reorientation of ACE2 toward the N-terminal domain in the same spike subunit as the RBD. Spike and ACE2 N-glycans exert synergistic effects, promoting better packing, strengthening the protein:protein interaction, and prolonging the residence time of the complex. ACE2 and heparin binding trigger rearrangement of the S29 functional site through allosteric interdomain communication. HS thus has a multifaceted role in facilitating SARS- CoV-2 infection.
Keywords	covid19
Language	English
Publishing date	2024-02-05
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.02.05.578888
Database	COVID19

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Article: Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos.

Guerra, Jessica / Belleri, Mirella / Paiardi, Giulia / Tobia, Chiara / Capoferri, Davide / Corli, Marzia / Scalvini, Elisa / Ghirimoldi, Marco / Manfredi, Marcello / Wade, Rebecca C / Presta, Marco / Mignani, Luca

Computational and structural biotechnology journal

2024 Volume 23, Page(s) 1397–1407

Abstract: Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients ... ...

Abstract	Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients and
Language	English
Publishing date	2024-03-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2024.03.023
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Iron Absorption in Celiac Disease and Nutraceutical Effect of 7-Hydroxymatairesinol. Mini-Review.

Zanella, Isabella / Paiardi, Giulia / Di Lorenzo, Diego / Biasiotto, Giorgio

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 9

Abstract: Anemia is the main extra-gastrointestinal symptom in inflammatory bowel diseases (IBDs). Interleukin-6 (IL-6) and other cytokines are secreted and act in the microenvironment of the small intestine mucous membrane of IBD patients. Iron is essential for ... ...

Abstract	Anemia is the main extra-gastrointestinal symptom in inflammatory bowel diseases (IBDs). Interleukin-6 (IL-6) and other cytokines are secreted and act in the microenvironment of the small intestine mucous membrane of IBD patients. Iron is essential for multiple cell functions and its homeostasis is regulated by the hepcidin-ferroportin axis. Hepcidin (HEPC) is mainly produced by the liver in response to iron needs but is also an acute phase protein. During inflammation, hepcidin is upregulated by IL-6 and is responsible for iron compartmentalization within cells, in turn causing anemia of inflammation. Tissues other than liver can produce hepcidin in response to inflammatory stimuli, in order to decrease iron efflux at a local level, then acting in an autocrine-paracrine manner. In IBDs and, in particular, in celiac disease (CeD), IL-6 might trigger the expression, upregulation and secretion of hepcidin in the small intestine, reducing iron efflux and exacerbating defective iron absorption. 7-Hydroxymatairesinol (7-HMR) belongs to the family of lignans, polyphenolic compounds produced by plants, and has nutraceutical antioxidant, anti-inflammatory and estrogenic properties. In this mini-review we revise the role of inflammation in IBDs and in particular in CeD, focusing our attention on the close link among inflammation, anemia and iron metabolism. We also briefly describe the anti-inflammatory and estrogenic activity of 7-HMR contained in foods that are often consumed by CeD patients. Finally, considering that HEPC expression is regulated by iron needs, inflammation and estrogens, we explored the hypothesis that 7-HMR consumption could ameliorate anemia in CeD using Caco-2 cells as bowel model. Further studies are needed to verify the regulation pathway through which 7-HMR may interfere with the local production of HEPC in bowel.
MeSH term(s)	Anemia/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Caco-2 Cells ; Celiac Disease/diet therapy ; Celiac Disease/immunology ; Celiac Disease/metabolism ; Cytokines/metabolism ; Edible Grain/chemistry ; Hepcidins/metabolism ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Inflammatory Bowel Diseases/diet therapy ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/metabolism ; Iron/metabolism ; Lignans/chemistry ; Lignans/metabolism ; Lignans/pharmacology
Chemical Substances	Anti-Inflammatory Agents ; Antioxidants ; Cytokines ; Hepcidins ; Lignans ; hydroxymatairesinol ; Iron (E1UOL152H7)
Language	English
Publishing date	2020-04-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25092041
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Article ; Online: A Bittersweet Computational Journey among Glycosaminoglycans.

Paiardi, Giulia / Milanesi, Maria / Wade, Rebecca C / D'Ursi, Pasqualina / Rusnati, Marco

Biomolecules

2021 Volume 11, Issue 5

Abstract: Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role ... ...

Abstract	Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the "bitter" and "sweet" aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge.
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Computational Biology/methods ; Extracellular Matrix/metabolism ; Glycosaminoglycans/chemistry ; Glycosaminoglycans/metabolism ; Humans ; Proteoglycans/chemistry ; Proteoglycans/metabolism ; Structure-Activity Relationship
Chemical Substances	Glycosaminoglycans ; Proteoglycans
Language	English
Publishing date	2021-05-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11050739
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Article ; Online: The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms.

Paiardi, Giulia / Richter, Stefan / Oreste, Pasqua / Urbinati, Chiara / Rusnati, Marco / Wade, Rebecca C

The Journal of biological chemistry

2021 Volume 298, Issue 2, Page(s) 101507

Abstract: Heparin, a naturally occurring glycosaminoglycan, has been found to have antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19. To elucidate the mechanistic basis for the antiviral ... ...

Abstract	Heparin, a naturally occurring glycosaminoglycan, has been found to have antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19. To elucidate the mechanistic basis for the antiviral activity of heparin, we investigated the binding of heparin to the SARS-CoV-2 spike glycoprotein by means of sliding window docking, molecular dynamics simulations, and biochemical assays. Our simulations show that heparin binds at long, positively charged patches on the spike glycoprotein, thereby masking basic residues of both the receptor-binding domain (RBD) and the multifunctional S1/S2 site. Biochemical experiments corroborated the simulation results, showing that heparin inhibits the furin-mediated cleavage of spike by binding to the S1/S2 site. Our simulations showed that heparin can act on the hinge region responsible for motion of the RBD between the inactive closed and active open conformations of the spike glycoprotein. In simulations of the closed spike homotrimer, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders opening. In simulations of open spike conformations, heparin induces stabilization of the hinge region and a change in RBD motion. Our results indicate that heparin can inhibit SARS-CoV-2 infection by three mechanisms: by allosterically hindering binding to the host cell receptor, by directly competing with binding to host heparan sulfate proteoglycan coreceptors, and by preventing spike cleavage by furin. Furthermore, these simulations provide insights into how host heparan sulfate proteoglycans can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Binding Sites ; COVID-19/drug therapy ; COVID-19/metabolism ; Heparin/chemistry ; Heparin/metabolism ; Heparin/pharmacology ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Antiviral Agents ; Spike Glycoprotein, Coronavirus ; spike glycoprotein, SARS-CoV ; Heparin (9005-49-6)
Language	English
Publishing date	2021-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.101507
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Article ; Online: Iron Absorption in Celiac Disease and Nutraceutical Effect of 7-Hydroxymatairesinol Mini-Review

Isabella Zanella / Giulia Paiardi / Diego Di Lorenzo / Giorgio Biasiotto

Molecules, Vol 25, Iss 2041, p

2020 Volume 2041

Abstract	Anemia is the main extra-gastrointestinal symptom in inflammatory bowel diseases (IBDs). Interleukin-6 (IL-6) and other cytokines are secreted and act in the microenvironment of the small intestine mucous membrane of IBD patients. Iron is essential for multiple cell functions and its homeostasis is regulated by the hepcidin–ferroportin axis. Hepcidin (HEPC) is mainly produced by the liver in response to iron needs but is also an acute phase protein. During inflammation, hepcidin is upregulated by IL-6 and is responsible for iron compartmentalization within cells, in turn causing anemia of inflammation. Tissues other than liver can produce hepcidin in response to inflammatory stimuli, in order to decrease iron efflux at a local level, then acting in an autocrine–paracrine manner. In IBDs and, in particular, in celiac disease (CeD), IL-6 might trigger the expression, upregulation and secretion of hepcidin in the small intestine, reducing iron efflux and exacerbating defective iron absorption. 7-Hydroxymatairesinol (7-HMR) belongs to the family of lignans, polyphenolic compounds produced by plants, and has nutraceutical antioxidant, anti-inflammatory and estrogenic properties. In this mini-review we revise the role of inflammation in IBDs and in particular in CeD, focusing our attention on the close link among inflammation, anemia and iron metabolism. We also briefly describe the anti-inflammatory and estrogenic activity of 7-HMR contained in foods that are often consumed by CeD patients. Finally, considering that HEPC expression is regulated by iron needs, inflammation and estrogens, we explored the hypothesis that 7-HMR consumption could ameliorate anemia in CeD using Caco-2 cells as bowel model. Further studies are needed to verify the regulation pathway through which 7-HMR may interfere with the local production of HEPC in bowel.
Keywords	7-Hydroxymatairesinol ; iron metabolism ; anemia ; hepcidin ; Inflammatory bowel Diseases ; Celiac Disease ; Organic chemistry ; QD241-441
Subject code	570 ; 610
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sialic acid as a target for the development of novel antiangiogenic strategies.

Chiodelli, Paola / Urbinati, Chiara / Paiardi, Giulia / Monti, Eugenio / Rusnati, Marco

Future medicinal chemistry

2018 Volume 10, Issue 24, Page(s) 2835–2854

Abstract: Sialic acid is associated with glycoproteins and gangliosides of eukaryotic cells. It regulates various molecular interactions, being implicated in inflammation and cancer, where its expression is regulated by sialyltransferases and sialidases. ... ...

Abstract	Sialic acid is associated with glycoproteins and gangliosides of eukaryotic cells. It regulates various molecular interactions, being implicated in inflammation and cancer, where its expression is regulated by sialyltransferases and sialidases. Angiogenesis, the formation of new capillaries, takes place during inflammation and cancer, and represents the outcome of several interactions occurring at the endothelial surface among angiogenic growth factors, inhibitors, receptors, gangliosides and cell-adhesion molecules. Here, we elaborate on the evidences that many structures involved in angiogenesis are sialylated and that their interactions depend on sialic acid with implications in angiogenesis itself, inflammation and cancer. We also discuss the possibility to exploit sialic acid as a target for the development of novel antiangiogenic drugs.
MeSH term(s)	Angiogenesis Inhibitors/chemistry ; Angiogenesis Inhibitors/pharmacology ; Animals ; Drug Discovery/methods ; Gangliosides/metabolism ; Glycoproteins/metabolism ; Humans ; Inflammation/complications ; Inflammation/drug therapy ; Inflammation/metabolism ; Models, Molecular ; Molecular Targeted Therapy/methods ; N-Acetylneuraminic Acid/metabolism ; Neoplasms/complications ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neovascularization, Pathologic/complications ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Gangliosides ; Glycoproteins ; N-Acetylneuraminic Acid (GZP2782OP0)
Language	English
Publishing date	2018-12-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc-2018-0298
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online: Three-fold mechanism of inhibition of SARS-CoV-2 infection by the interaction of the spike glycoprotein with heparin

Paiardi, Giulia / Richter, Stefan / Oreste, Pasqua / Urbinati, Chiara / Rusnati, Marco / Wade, Rebecca C.

2021

Abstract: Heparin has been found to have antiviral activity against SARS-CoV-2. Here, by means of sliding window docking, molecular dynamics simulations and biochemical assays, we investigate the binding mode of heparin to the virus spike glycoprotein and the ... ...

Abstract	Heparin has been found to have antiviral activity against SARS-CoV-2. Here, by means of sliding window docking, molecular dynamics simulations and biochemical assays, we investigate the binding mode of heparin to the virus spike glycoprotein and the molecular basis for its antiviral activity. The simulations show that heparin binds at long, mostly positively charged patches on the spike, thereby masking the basic residues of the receptor binding domain and of the S1/S2 site. Experiments corroborated the simulation results by showing that heparin inhibits the cleavage of spike by furin by binding to the basic S1/S2 site. Our results indicate that heparin exerts its antiviral activity by both direct and allosteric mechanisms. Furthermore, the simulations provide insights into how heparan sulfate proteoglycans on the host cell can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.
Keywords	Quantitative Biology - Biomolecules
Subject code	612
Publishing date	2021-03-13
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction: Cholenic acid derivative UniPR1331 impairs tumor angiogenesis via blockade of VEGF/VEGFR2 in addition to Eph/ephrin.

Rusnati, Marco / Paiardi, Giulia / Tobia, Chiara / Urbinati, Chiara / Lodola, Alessio / D'Ursi, Pasqualina / Corrado, Miriam / Castelli, Riccardo / Wade, Rebecca C / Tognolini, Massimiliano / Chiodelli, Paola

Cancer gene therapy

2021 Volume 29, Issue 7, Page(s) 1070

Language	English
Publishing date	2021-09-30
Publishing country	England
Document type	Published Erratum
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-021-00391-9
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Zs.A 4125: Show issues

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Article ; Online: Glycosaminoglycans: What Remains To Be Deciphered?

Perez, Serge / Makshakova, Olga / Angulo, Jesus / Bedini, Emiliano / Bisio, Antonella / de Paz, Jose Luis / Fadda, Elisa / Guerrini, Marco / Hricovini, Michal / Hricovini, Milos / Lisacek, Frederique / Nieto, Pedro M / Pagel, Kevin / Paiardi, Giulia / Richter, Ralf / Samsonov, Sergey A / Vivès, Romain R / Nikitovic, Dragana / Ricard Blum, Sylvie

JACS Au

2023 Volume 3, Issue 3, Page(s) 628–656

Abstract: Glycosaminoglycans (GAGs) are complex polysaccharides exhibiting a vast structural diversity and fulfilling various functions mediated by thousands of interactions in the extracellular matrix, at the cell surface, and within the cells where they have ... ...

Abstract	Glycosaminoglycans (GAGs) are complex polysaccharides exhibiting a vast structural diversity and fulfilling various functions mediated by thousands of interactions in the extracellular matrix, at the cell surface, and within the cells where they have been detected in the nucleus. It is known that the chemical groups attached to GAGs and GAG conformations comprise "glycocodes" that are not yet fully deciphered. The molecular context also matters for GAG structures and functions, and the influence of the structure and functions of the proteoglycan core proteins on sulfated GAGs and vice versa warrants further investigation. The lack of dedicated bioinformatic tools for mining GAG data sets contributes to a partial characterization of the structural and functional landscape and interactions of GAGs. These pending issues will benefit from the development of new approaches reviewed here, namely (i) the synthesis of GAG oligosaccharides to build large and diverse GAG libraries, (ii) GAG analysis and sequencing by mass spectrometry (
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2691-3704
ISSN (online)	2691-3704
DOI	10.1021/jacsau.2c00569
Database	MEDical Literature Analysis and Retrieval System OnLINE

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