Changes in total charge on spike protein of SARS-CoV-2 in emerging lineages DOI Creative Commons
Anže Božič, Rudolf Podgornik

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 23, 2023

Motivation: Charged amino acid residues on the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to influence its binding different cell surface receptors, non-specific electrostatic interactions with environment, and structural stability conformation. It is therefore important obtain a good understanding mutations that affect total charge which arisen across SARS-CoV-2 lineages during course virus' evolution. Results: We analyse change in number ionizable acids corresponding proteins almost 2200 emerged over span pandemic. Our results show previously observed trend toward an increase positive variants concern has essentially stopped emergence early omicron variants. Furthermore, recently greater diversity terms their composition acids. also demonstrate patterns are characteristic related within broader clade division phylogenetic tree. Due ubiquity biological our findings relevant for broad range studies dealing environment. Availability: The data underlying article available online Supplementary Material.

Язык: Английский

Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow DOI Creative Commons
Jacques Fantini, Fodil Azzaz, Coralie Di Scala

и другие.

Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown, С. 108797 - 108797

Опубликована: Янв. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Язык: Английский

Процитировано

2
Changes in total charge on spike protein of SARS-CoV-2 in emerging lineages DOI Creative Commons
Anže Božič, Rudolf Podgornik

Bioinformatics Advances, Год журнала: 2024, Номер 4(1)

Опубликована: Янв. 1, 2024

Abstract Motivation Charged amino acid residues on the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to influence its binding different cell surface receptors, non-specific electrostatic interactions with environment, and structural stability conformation. It is therefore important obtain a good understanding mutations that affect total charge which arisen across SARS-CoV-2 lineages during course virus’ evolution. Results We analyse change in number ionizable acids corresponding proteins almost 2200 emerged over span pandemic. Our results show previously observed trend toward an increase positive variants concern has essentially stopped emergence early omicron variants. Furthermore, recently greater diversity terms their composition acids. also demonstrate patterns are characteristic related within broader clade division phylogenetic tree. Due ubiquity biological our findings relevant for broad range studies dealing environment. Availability implementation The data underlying article available Supplementary material.

Язык: Английский

Процитировано

8
Resistance‐associated mutations to the anti‐SARS‐CoV‐2 agent nirmatrelvir: Selection not induction DOI Creative Commons
Philippe Colson,

Jérémy Delerce,

Pierre Pontarotti

и другие.

Journal of Medical Virology, Год журнала: 2024, Номер 96(2)

Опубликована: Фев. 1, 2024

Abstract Mutations associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) resistance to antiprotease nirmatrelvir were reported. We aimed detect them in SARS‐CoV‐2 genomes and quasispecies retrieved our institute before drug availability January 2022 analyze the impact of mutations on protease (3CLpro) structure. sought for 38 3CLpro a set 62 673 obtained from samples collected between 2020 2023 these 90 2020, using Python. major mutation E166V was generated Swiss Pdb Viewer Molegro Molecular Viewer. detected 22 (58%) resistance‐associated 417 (0.67%) analyzed; 325 (78%) had been 2020−2021. APOBEC signatures found 12/22 mutations. also among viral some minority reads harboring any 15 mutations, including E166V. Also, we predicted that has very limited effect structure but may prevent attachment. Thus, evidenced pre‐existed availability. These findings further warrant genomic surveillance characterization.

Язык: Английский

Процитировано

4
What Is life? Rethinking Biology in Light of Fundamental Parameters DOI Creative Commons
Jacques Fantini,

Mélanie Matveeva,

Marine Lefebvre

и другие.

Life, Год журнала: 2024, Номер 14(3), С. 280 - 280

Опубликована: Фев. 20, 2024

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 paradoxical situation where one can describe at the atomic level complex objects remain globally poorly defined. One could assume such descriptions make it possible to perfectly characterize living systems. However, many cases misinterpretation put this assumption into perspective. In article, we focus on critical parameters as time, water, entropy, space, quantum properties, electrostatic potential redefine nature matter, with special emphasis biological coding. Where does DNA double helix come from, why cannot reproduction organisms occur without mutations, what are limitations genetic code, do not all proteins have stable three-dimensional structure? There so questions be resolved considering aforementioned parameters. Indeed, (i) time space constrain mechanisms impose drastic solutions beings (enzymes, transporters); (ii) water controls fidelity replication structure/disorder balance proteins; (iii) entropy driving force enzymatic reactions molecular interactions; (iv) explain molecule simple hydrocyanic acid (HCN) foreshadows helical structure DNA, how stabilized, mutations occur, Earth magnetic field influence migration birds; (v) epigenetic mechanisms, lipid raft functions, virus infections. We consider raising awareness these basic better understanding is, handles order chaos through combination mechanisms. Thus, propose incorporate definition life.

Язык: Английский

Процитировано

4
Glutamate, Gangliosides, and the Synapse: Electrostatics at Work in the Brain DOI Open Access
Henri Chahinian, Nouara Yahi, Jacques Fantini

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 8583 - 8583

Опубликована: Авг. 6, 2024

The synapse is a piece of information transfer machinery replacing the electrical conduction nerve impulses at end neuron. Like many biological mechanisms, its functioning heavily affected by time constraints. solution selected evolution based on chemical communication that, in theory, cannot compete with speed conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through high concentrations neurotransmitters inside synaptic vesicles; (ii) concentration neurotransmitter receptors lipid rafts, which are signaling platforms; indeed, presence raft lipids, such as gangliosides cholesterol, allows fine tuning these lipids; (iii) negative charges gangliosides, generate an attractive (for cationic neurotransmitters, serotonin) or repulsive anionic glutamate) electric field. This field controls flow glutamate tripartite involving pre- post-synaptic neurons astrocyte. Changes expression brain can disrupt glutamatergic synapse, causing fatal diseases, Rett syndrome. In review, we propose in-depth analysis role highlighting primordial generally overlooked played gangliosides.

Язык: Английский

Процитировано

4
Five‐Year (2017–2022) Evolutionary Dynamics of Human Coronavirus HKU1 in Southern France With Emergence of Viruses Harboring Spike H512R Substitution DOI Creative Commons

Houmadi Hikmat,

Lorlane Le Targa,

Céline Boschi

и другие.

Journal of Medical Virology, Год журнала: 2025, Номер 97(2)

Опубликована: Фев. 1, 2025

ABSTRACT HCoV‐HKU1 diversity and evolution were scarcely studied. We performed next‐generation sequencing (NGS) analysis of genomes over 5 years. NGS used Illumina technology on NovaSeq 6000 following whole genome PCR amplification by an in‐house set primers designed using Gemi PrimalScheme. Genome assembly analyses CLC Genomics, Mafft, BioEdit, Nextstrain, Nextclade, MEGA, iTol bioinformatic tools. Spike molecular modeling dynamics simulations Molegro Molecular Viewer Hyperchem programs. Twenty‐eight systems allowed obtaining 158 including 69 89 genotypes A B, respectively. Both co‐circulated during the study period but one predominated each year. total 1683 amino acid substitutions 80 in ≥ 10 detected genotype relatively to a 2004 reference. H512R spike, first 2009 reported as involved antibody neutralization, was found all A, almost always with V387I K478N, predicted here significantly improve cellular TMPRSS2 protein binding. Also, 1802 64 B 2005 This substantially expands global genomes. Genomics structural contributed our understanding evolution.

Язык: Английский

Процитировано

0
Increased preference for lysine over arginine in spike proteins of SARS-CoV-2 BA.2.86 variant and its daughter lineages DOI Creative Commons
Anže Božič, Rudolf Podgornik

PLoS ONE, Год журнала: 2025, Номер 20(4), С. e0320891 - e0320891

Опубликована: Апрель 7, 2025

The COVID-19 pandemic offered an unprecedented glimpse into the evolution of its causative virus, SARS-CoV-2. It has been estimated that since outbreak in late 2019, virus explored all possible alternatives terms missense mutations for sites polypeptide chain. Spike protein exhibits largest sequence variation particular, with many individual impacting target recognition, cellular entry, and endosomal escape virus. Moreover, recent studies unveiled a significant increase total charge on spike during initial period pandemic. While this trend recently come to halt, we perform sequence-based analysis 2665 SARS-CoV-2 variants which shows ionizable amino acids continue occur newly emerging variants, notable differences between lineages from different clades. What is more, show within can acquire positive charge, prominent preference lysine residues over arginine residues. This lysine-to-arginine ratio increased at several points evolution, most BA.2.86 sublineages, including dominant JN.1, KP.3, XEC variants. consequence structural regions now among highest viral species Coronaviridae family. impact high proteins daughter fitness remains unclear; discuss potential mechanisms could play role serve as starting point further studies.

Язык: Английский

Процитировано

0
Lipid rafts: novel therapeutic targets for metabolic, neurodegenerative, oncological, and cardiovascular diseases DOI Creative Commons
Mohamad Warda, Samet Tekin, Mahmoud Gamal

и другие.

Lipids in Health and Disease, Год журнала: 2025, Номер 24(1)

Опубликована: Апрель 17, 2025

Lipid rafts are specialized microdomains within cellular membranes enriched with cholesterol and sphingolipids that play key roles in organization, signaling, homeostasis. This review highlights their involvement protein clustering, energy metabolism, oxidative stress responses, inflammation, autophagy, apoptosis. These findings clarify influence on trafficking, adhesion while interacting the extracellular matrix, cytoskeleton, ion channels, making them pivotal progression of various diseases. further addresses contributions to immune including autoimmune diseases, chronic cytokine storms. Additionally, role as entry points for pathogens has been demonstrated, raft-associated receptors being exploited by viruses bacteria increase infectivity evade defenses. Disruptions lipid raft dynamics linked signaling defects, which contribute metabolic, neurodegenerative, cardiovascular underscores potential therapeutic targets, discussing innovations such engineered transplantation. Advances analytical techniques mass spectrometry have expanded our understanding composition dynamics, opening new directions research. By consolidating current insights, we highlight need exploration molecular mechanisms.

Язык: Английский

Процитировано

0
The Bioactive Sphingolipid Playbook. A Primer for the Uninitiated as well as Sphingolipidologists DOI Creative Commons
Yusuf A. Hannun, Alfred H. Merrill,

Chiara Luberto

и другие.

Journal of Lipid Research, Год журнала: 2025, Номер unknown, С. 100813 - 100813

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives DOI Creative Commons
Jacques Fantini

Receptors, Год журнала: 2024, Номер 3(1), С. 107 - 121

Опубликована: Март 18, 2024

Receptology, the science of receptors, is a multidimensional field research which can be dissected into biosynthesis, membrane sorting, ligand binding and signal transduction. Plasma receptors connect cells with their environment transmit signals that are translated biological information. The historical paradigm ligand–receptor interactions lock-and-key model. This model presupposes both partners have precise 3D shape perfectly fits together to form complex. However, this simple suffers from severe limitations due several levels simplifications: (i) water molecules lipids not considered; (ii) all ligands stable structure; (iii) ligand-binding pocket receptor often flexible conformationally rearranged after initial step (induced fit mechanism) and/or subjected conformational selection by ligand; (iv) there transduction mechanisms either purely mechanical (conformational change induced ligand), lipid-assisted (e.g., raft such as cholesterol or gangliosides), in some instances quantic nature (detection odorant molecules). aim present review challenge old paradigms new concepts receptology consider impact critical parameters molecules, lipids, electrostatic surface potential quantum mechanisms.

Язык: Английский

Процитировано

3