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Article ; Online: Lipid rafts and human diseases: why we need to target gangliosides.

Fantini, Jacques

2023 Volume 13, Issue 9, Page(s) 1636–1650

Abstract: Gangliosides are functional components of membrane lipid rafts that control critical functions in cell communication. Many pathologies involve raft gangliosides, which therefore represent an approach of choice for developing innovative therapeutic ... ...

Abstract	Gangliosides are functional components of membrane lipid rafts that control critical functions in cell communication. Many pathologies involve raft gangliosides, which therefore represent an approach of choice for developing innovative therapeutic strategies. Beginning with a discussion of what a disease is (and is not), this review lists the major human pathologies that involve gangliosides, which includes cancer, diabetes, and infectious and neurodegenerative diseases. In most cases, the problem is due to a protein whose binding to gangliosides either creates a pathological condition or impairs a physiological function. Then, I draw up an inventory of the different molecular mechanisms of protein-ganglioside interactions. I propose to classify the ganglioside-binding domains of proteins into four categories, which I name GBD-1, GBD-2, GBD-3, and GBD-4. This structural and functional classification could help to rationalize the design of innovative molecules capable of disrupting the binding of selected proteins to gangliosides without generating undesirable effects. The biochemical specificities of gangliosides expressed in the human brain must also be taken into account to improve the reliability of animal models (or any animal-free alternative) of Alzheimer's and Parkinson's diseases.
MeSH term(s)	Humans ; Gangliosides/metabolism ; Reproducibility of Results ; Parkinson Disease/pathology ; Brain/metabolism ; Membrane Microdomains/chemistry ; Membrane Microdomains/metabolism
Chemical Substances	Gangliosides
Language	English
Publishing date	2023-04-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2651702-4
ISSN	2211-5463 ; 2211-5463
ISSN (online)	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13612
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book: Brain lipids in synaptic function and neurological disease

Fantini, Jacques / Yahi, Nouara

clues to innovative therapeutic strategies for brain disorders

2015

Author's details	Jacques Fantini ; Nouara Yahi
Keywords	Brain/Physiology ; Lipids/Physiological effect ; Brain/Diseases/Pathophysiology ; Synapses
Subject code	612.82
Language	English
Size	XV, 381 S. : zahlr. Ill., graph. Darst., 24 cm
Publisher	Elsevier Acad. Press
Publishing place	Amsterdam u.a.
Publishing country	Netherlands
Document type	Book
Note	Includes bibliographical references
Accompanying material	Hinweis auf zusätzliches Internetmaterial im Buch
HBZ-ID	HT018712730
ISBN	978-0-12-800111-0 ; 0-12-800111-9
Database	Catalogue ZB MED Medicine, Health

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Shelf mark	Loan status	Location
2015 A 2686	available for loan (reading room)	Lesesaal EG

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Article ; Online: Possible contribution of rare alleles of human ACE2 in the emergence of SARS-CoV-2 variants escaping the immune response.

Devaux, Christian A / Fantini, Jacques

Frontiers in immunology

2023 Volume 14, Page(s) 1252367

Abstract: Since the start of the SARS-CoV-2 pandemic, the rapid replacement of one lineage by another has been observed. Indeed, SARS-CoV-2 is evolving through a quasispecies mechanism leading to post-infection mutation selection under positive evolutionary ... ...

Abstract	Since the start of the SARS-CoV-2 pandemic, the rapid replacement of one lineage by another has been observed. Indeed, SARS-CoV-2 is evolving through a quasispecies mechanism leading to post-infection mutation selection under positive evolutionary pressure (host-driven viral evolution). These mutations may reduce the effectiveness of the specific neutralizing immune response against the virus. We provide here evidence that apart from the selection of SARS-CoV-2 variants by the immune system, selection by the cellular receptor can just as well select variants which escape neutralization.
MeSH term(s)	Humans ; Alleles ; Angiotensin-Converting Enzyme 2/genetics ; COVID-19/immunology ; SARS-CoV-2
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; ACE2 protein, human (EC 3.4.17.23)
Language	English
Publishing date	2023-10-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1252367
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Article: Unravelling Antigenic Cross-Reactions toward the World of Coronaviruses: Extent of the Stability of Shared Epitopes and SARS-CoV-2 Anti-Spike Cross-Neutralizing Antibodies.

Devaux, Christian A / Fantini, Jacques

Pathogens (Basel, Switzerland)

2023 Volume 12, Issue 5

Abstract: The human immune repertoire retains the molecular memory of a very great diversity of target antigens (epitopes) and can recall this upon a second encounter with epitopes against which it has previously been primed. Although genetically diverse, proteins ...

Abstract	The human immune repertoire retains the molecular memory of a very great diversity of target antigens (epitopes) and can recall this upon a second encounter with epitopes against which it has previously been primed. Although genetically diverse, proteins of coronaviruses exhibit sufficient conservation to lead to antigenic cross-reactions. In this review, our goal is to question whether pre-existing immunity against seasonal human coronaviruses (HCoVs) or exposure to animal CoVs has influenced the susceptibility of human populations to SARS-CoV-2 and/or had an impact upon the physiopathological outcome of COVID-19. With the hindsight that we now have regarding COVID-19, we conclude that although antigenic cross-reactions between different coronaviruses exist, cross-reactive antibody levels (titers) do not necessarily reflect on memory B cell frequencies and are not always directed against epitopes which confer cross-protection against SARS-CoV-2. Moreover, the immunological memory of these infections is short-term and occurs in only a small percentage of the population. Thus, in contrast to what might be observed in terms of cross-protection at the level of a single individual recently exposed to circulating coronaviruses, a pre-existing immunity against HCoVs or other CoVs can only have a very minor impact on SARS-CoV-2 circulation at the level of human populations.
Language	English
Publishing date	2023-05-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens12050713
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Article: ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus.

Devaux, Christian A / Fantini, Jacques

Frontiers in microbiology

2023 Volume 14, Page(s) 1199561

Abstract: Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from ... ...

Abstract	Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus's affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare E
Language	English
Publishing date	2023-07-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2023.1199561
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Article: What Is life? Rethinking Biology in Light of Fundamental Parameters.

Fantini, Jacques / Matveeva, Mélanie / Lefebvre, Marine / Chahinian, Henri

Life (Basel, Switzerland)

2024 Volume 14, Issue 3

Abstract: Defining life is an arduous task that has puzzled philosophers and scientists for centuries. Yet biology suffers from a lack of clear definition, putting biologists in a paradoxical situation where one can describe at the atomic level complex objects ... ...

Abstract	Defining life is an arduous task that has puzzled philosophers and scientists for centuries. Yet biology suffers from a lack of clear definition, putting biologists in a paradoxical situation where one can describe at the atomic level complex objects that remain globally poorly defined. One could assume that such descriptions make it possible to perfectly characterize living systems. However, many cases of misinterpretation put this assumption into perspective. In this article, we focus on critical parameters such as time, water, entropy, space, quantum properties, and electrostatic potential to redefine the nature of living matter, with special emphasis on biological coding. Where does the DNA double helix come from, why cannot the reproduction of living organisms occur without mutations, what are the limitations of the genetic code, and why do not all proteins have a stable three-dimensional structure? There are so many questions that cannot be resolved without considering the aforementioned parameters. Indeed, (i) time and space constrain many biological mechanisms and impose drastic solutions on living beings (enzymes, transporters); (ii) water controls the fidelity of DNA replication and the structure/disorder balance of proteins; (iii) entropy is the driving force of many enzymatic reactions and molecular interactions; (iv) quantum mechanisms explain why a molecule as simple as hydrocyanic acid (HCN) foreshadows the helical structure of DNA, how DNA is stabilized, why mutations occur, and how the Earth magnetic field can influence the migration of birds; (v) electrostatic potential controls epigenetic mechanisms, lipid raft functions, and virus infections. We consider that raising awareness of these basic parameters is critical for better understanding what life is, and how it handles order and chaos through a combination of genetic and epigenetic mechanisms. Thus, we propose to incorporate these parameters into the definition of life.
Language	English
Publishing date	2024-02-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life14030280
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Article ; Online: The epigenetic dimension of protein structure.

Azzaz, Fodil / Fantini, Jacques

Biomolecular concepts

2022 Volume 13, Issue 1, Page(s) 55–60

Abstract: Accurate prediction of protein structure is one of the most challenging goals of biology. The most recent achievement is AlphaFold, a machine learning method that has claimed to have solved the structure of almost all human proteins. This technological ... ...

Abstract	Accurate prediction of protein structure is one of the most challenging goals of biology. The most recent achievement is AlphaFold, a machine learning method that has claimed to have solved the structure of almost all human proteins. This technological breakthrough has been compared to the sequencing of the human genome. However, this triumphal statement should be treated with caution, as we identified serious flaws in some AlphaFold models. Disordered regions are often represented by large loops that clash with the overall protein geometry, leading to unrealistic structures, especially for membrane proteins. In fact, AlphaFold comes up against the notion that protein folding is not solely determined by genomic information. We suggest that all parameters controlling the structure of a protein without being strictly encoded in its amino acid sequence should be coined "epigenetic dimension of protein structure." Such parameters include for instance protein solvation by membrane lipids, or the structuration of disordered proteins upon ligand binding, but exclude sequence-encoded sites of post-translational modifications such as glycosylation. In our view, this paradigm is necessary to reconcile two opposite properties of living systems: beyond rigorous biological coding, evolution has given way to a certain level of uncertainty and anarchy.
MeSH term(s)	Amino Acid Sequence ; Epigenesis, Genetic ; Humans ; Membrane Proteins ; Protein Conformation ; Protein Folding
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2022-02-21
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2557908-3
ISSN	1868-503X ; 1868-5021
ISSN (online)	1868-503X
ISSN	1868-5021
DOI	10.1515/bmc-2022-0006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Convergent Evolution Dynamics of SARS-CoV-2 and HIV Surface Envelope Glycoproteins Driven by Host Cell Surface Receptors and Lipid Rafts: Lessons for the Future.

Fantini, Jacques / Chahinian, Henri / Yahi, Nouara

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: Although very different, in terms of their genomic organization, their enzymatic proteins, and their structural proteins, HIV and SARS-CoV-2 have an extraordinary evolutionary potential in common. Faced with various selection pressures that may be ... ...

Abstract	Although very different, in terms of their genomic organization, their enzymatic proteins, and their structural proteins, HIV and SARS-CoV-2 have an extraordinary evolutionary potential in common. Faced with various selection pressures that may be generated by treatments or immune responses, these RNA viruses demonstrate very high adaptive capacities, which result in the continuous emergence of variants and quasi-species. In this retrospective analysis of viral proteins, ensuring the adhesion of these viruses to the plasma membrane of host cells, we highlight many common points that suggest the convergent mechanisms of evolution. HIV and SARS-CoV-2 first recognize a lipid raft microdomain that acts as a landing strip for viral particles on the host cell surface. In the case of mucosal cells, which are the primary targets of both viruses, these microdomains are enriched in anionic glycolipids (gangliosides) forming a global electronegative field. Both viruses use lipid rafts to surf on the cell surface in search of a protein receptor able to trigger the fusion process. This implies that viral envelope proteins are both geometrically and electrically compatible to the biomolecules they select to invade host cells. In the present study, we identify the surface electrostatic potential as a critical parameter controlling the convergent evolution dynamics of HIV-1 and SARS-CoV-2 surface envelope proteins, and we discuss the impact of this parameter on the phenotypic properties of both viruses. The virological data accumulated since the emergence of HIV in the early 1980s should help us to face present and future virus pandemics.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19/metabolism ; Retrospective Studies ; Viral Proteins/metabolism ; Receptors, Cell Surface/metabolism ; Antigens, Viral/metabolism ; HIV Infections/metabolism ; Membrane Microdomains/metabolism ; Glycoproteins/metabolism
Chemical Substances	Viral Proteins ; Receptors, Cell Surface ; Antigens, Viral ; Glycoproteins
Language	English
Publishing date	2023-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24031923
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Article ; Online: Electrostatic Surface Potential as a Key Parameter in Virus Transmission and Evolution: How to Manage Future Virus Pandemics in the Post-COVID-19 Era.

Fantini, Jacques / Azzaz, Fodil / Chahinian, Henri / Yahi, Nouara

Viruses

2023 Volume 15, Issue 2

Abstract: Virus-cell interactions involve fundamental parameters that need to be considered in strategies implemented to control viral outbreaks. Among these, the surface electrostatic potential can give valuable information to deal with new epidemics. In this ... ...

Abstract	Virus-cell interactions involve fundamental parameters that need to be considered in strategies implemented to control viral outbreaks. Among these, the surface electrostatic potential can give valuable information to deal with new epidemics. In this article, we describe the role of this key parameter in the hemagglutination of red blood cells and in the co-evolution of synaptic receptors and neurotransmitters. We then establish the functional link between lipid rafts and the electrostatic potential of viruses, with special emphasis on gangliosides, which are sialic-acid-containing, electronegatively charged plasma membrane components. We describe the common features of ganglioside binding domains, which include a wide variety of structures with little sequence homology but that possess key amino acids controlling ganglioside recognition. We analyze the role of the electrostatic potential in the transmission and intra-individual evolution of HIV-1 infections, including gatekeeper and co-receptor switch mechanisms. We show how to organize the epidemic surveillance of influenza viruses by focusing on mutations affecting the hemagglutinin surface potential. We demonstrate that the electrostatic surface potential, by modulating spike-ganglioside interactions, controls the hemagglutination properties of coronaviruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) as well as the structural dynamics of SARS-CoV-2 evolution. We relate the broad-spectrum antiviral activity of repositioned molecules to their ability to disrupt virus-raft interactions, challenging the old concept that an antibiotic or anti-parasitic cannot also be an antiviral. We propose a new concept based on the analysis of the electrostatic surface potential to develop, in real time, therapeutic and vaccine strategies adapted to each new viral epidemic.
MeSH term(s)	Humans ; Pandemics/prevention & control ; COVID-19/epidemiology ; COVID-19/prevention & control ; SARS-CoV-2/genetics ; Static Electricity ; Antiviral Agents ; Gangliosides
Chemical Substances	Antiviral Agents ; Gangliosides
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15020284
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Article ; Online: Structural basis of botulinum neurotoxin serotype A1 binding to human SV2A or SV2C receptors.

Azzaz, Fodil / Hilaire, Didier / Fantini, Jacques

Chemico-biological interactions

2023 Volume 373, Page(s) 110384

Abstract: Botulinum neurotoxin A1 (BoNT/A1) is the most potent natural poison in human. BoNT/A1 recognize the luminal domain of SV2A (LD-SV2A) and its glycosylation at position N573 (N573g) or the luminal domain of SV2C (LD-SV2C) and its glycosylation at position ... ...

Abstract	Botulinum neurotoxin A1 (BoNT/A1) is the most potent natural poison in human. BoNT/A1 recognize the luminal domain of SV2A (LD-SV2A) and its glycosylation at position N573 (N573g) or the luminal domain of SV2C (LD-SV2C) and its glycosylation at position N559 (N559g) to bind neural membrane. Our computational data suggest that the N-glycan at position 480 (N480g) in the luminal domain of SV2C (LD-SV2C) indirectly enhanced the contacts of the neurotoxin surface with the second N-glycan at position 559 (N559g) by acting as a shield to prevent N559g to interact with residues of LD-SV2C. The absence of an N-glycan homologous to N480g in LD-SV2A leads to a decrease of the binding of N573g to the surface of BoNT/A1. Concerning the intermolecular interactions between BoNT/A and the protein part of LD-SV2A or LD-SV2C, we showed that the high affinity of the neurotoxin for binding LD-SV2C are mediated by a better compaction of its F557-F562 part provided by a π-π network mediated by residues F547, F552, F557 and F562 coupled with the presence of two aromatic residues at position 563 and 564 that optimize the binding of BoNT/A1 via cation-pi and CH-pi interaction. Finally, in addition to the well-known ganglioside binding site which accommodates a ganglioside on the surface of BoNT/A1, we identified a structure we coined the ganglioside binding loop defined by the sequence 1253-HQFNNIAK-1260 that is conserved across all subtypes of BoNT/A and is predicted to has a high affinity to interact with gangliosides. These data solved the puzzle generated by mutational studies that could be only partially understood with crystallographic data that lack both a biologically relevant membrane environment and a full glycosylation of SV2.
MeSH term(s)	Humans ; Neurotoxins ; Serogroup ; Protein Binding ; Binding Sites ; Gangliosides ; Membrane Glycoproteins/metabolism ; Nerve Tissue Proteins/metabolism
Chemical Substances	Neurotoxins ; MP35N alloy (12646-94-5) ; Gangliosides ; SV2A protein, human (148845-93-6) ; Membrane Glycoproteins ; Nerve Tissue Proteins ; SV2C protein, human
Language	English
Publishing date	2023-02-06
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2023.110384
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