The SARS-CoV-2 Spike Glycoprotein Directly Binds Exogeneous Sialic Acids: A NMR View

[EN] The interaction of the SARS CoV2 spike glycoprotein with two sialic acid-containing trisaccharides (alpha 2,3 and alpha 2,6 sialyl N-acetyllactosamine) has been demonstrated by NMR. The NMR-based distinction between the signals of those sialic acids in the glycans covalently attached to the spike protein and those belonging to the exogenous alpha 2,3 and alpha 2,6 sialyl N-acetyllactosamine ligands has been achieved by synthesizing uniformly C-13-labelled trisaccharides at the sialic acid and galactose moieties. STD-H-1,C-13-HSQC NMR experiments elegantly demonstrate the direct interaction of the sialic acid residues of both trisaccharides with additional participation of the galactose moieties, especially for the alpha 2,3-linked analogue. Additional experiments with the spike protein in the presence of a specific antibody for the N-terminal domain and with the isolated receptor binding and N-terminal domains of the spike protein unambiguously show that the sialic acid binding site is located at the N-terminal domain.This research was funded by the European Research Council (ERC-2017-AdG, project number 788143-RECGLYCA NMR to J.J.B.) and Agencia Estatal de Investigacion (Spain), projects RTI2018-094751-B-C21 to J.J.B. & A.A. and PID2019-107770RA-I00 to J.E.O., and by the Human Frontier Science Program (HFSP; grant LT000747/2018-C to L.U.) and CIBER, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spai

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

BACKGROUND: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. METHODS: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. FINDINGS: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. INTERPRETATION: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. FUNDING: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR)

H2S biosynthesis and catabolism: new insights from molecular studies

Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissue

Recent advances in the application of NMR methodologies to analyze the conformation, dynamics, and interactions of saccharides

25 p.-7 fig. Carbohydrate Chemistry: Chemical and Biological Approaches.Volume 44. Editors: Amélia Pilar Rauter, Thisbe K Lindhorst, Yves QueneauThis chapter is dedicated to the presentation of different examples of the application of solution NMR to the study of conformation, dynamics of sugar molecules (oligo and polysaccharides, glycopeptides and glycomimetics) including the investigation of glycanrelated molecular recognition events. It is not our intention to be exhaustive, rather to highlight diverse examples since 2016. They are presented depending on the chemical nature of the saccharide molecule, and on the different methodologies that can be employed.We thank MINECO (Spain, Projects) and the European Union (Project RECGLYCANMR and BACTIVAX) for financial support. AF also thanksMINECO for Juan de la Cierva contract.Peer reviewe