A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

K+ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K+ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2′-((5,5′(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2′carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K+ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis

DomPep—A General Method for Predicting Modular Domain-Mediated Protein-Protein Interactions

Protein-protein interactions (PPIs) are frequently mediated by the binding of a modular domain in one protein to a short, linear peptide motif in its partner. The advent of proteomic methods such as peptide and protein arrays has led to the accumulation of a wealth of interaction data for modular interaction domains. Although several computational programs have been developed to predict modular domain-mediated PPI events, they are often restricted to a given domain type. We describe DomPep, a method that can potentially be used to predict PPIs mediated by any modular domains. DomPep combines proteomic data with sequence information to achieve high accuracy and high coverage in PPI prediction. Proteomic binding data were employed to determine a simple yet novel parameter Ligand-Binding Similarity which, in turn, is used to calibrate Domain Sequence Identity and Position-Weighted-Matrix distance, two parameters that are used in constructing prediction models. Moreover, DomPep can be used to predict PPIs for both domains with experimental binding data and those without. Using the PDZ and SH2 domain families as test cases, we show that DomPep can predict PPIs with accuracies superior to existing methods. To evaluate DomPep as a discovery tool, we deployed DomPep to identify interactions mediated by three human PDZ domains. Subsequent in-solution binding assays validated the high accuracy of DomPep in predicting authentic PPIs at the proteome scale. Because DomPep makes use of only interaction data and the primary sequence of a domain, it can be readily expanded to include other types of modular domains

Rhéa : entrepôt de données et aide à la décision pour les services de réanimation

noteInternational audienceresum

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

K⁺ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K⁺ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi­(2-pyrrolyl)­methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2′-((5,5′(di-<i>p</i>-topyldiaryldi­(2-pyrrolyl)­methane)­bis­(2,2′carbonyl)­bis­(azanediyl)) diethaneamine·2HCl] (<b>8</b>) selectively blocked Kv1.1 channels (IC₅₀ ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K⁺ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis

Améliorer sa récupération en sport

En quelques décennies, la récupération du sportif de haut niveau s'est définitivement imposée comme un enjeu majeur. D'une part parce qu'il est essentiel de préserver la santé de l'athlète, d'autre part parce que la réitération de la performance, parfois sur de très courts laps de temps, requiert une parfaite récupération entre les épreuves. Aux méthodes de récupération parfois anciennes - certaines d'entre elles remontent...à l'Antiquité ! - viennent s'ajouter des techniques particulièrement innovantes. À tel point que l'encadrement médical d'un athlète dispose à présent d'un vaste panel de méthodes : récupération active ou passive, étirements, massages, électrostimulation, luminothérapie, aromathérapie, application de chaud ou de froid, cryothérapie, hydrothérapie, sauna, hammam, infrarouges, nutrition et réhydratation… Pour autant, il n'est pas toujours facile de distinguer les méthodes véritablement efficaces des chimères dont certaines peuvent s'avérer inopérantes, voire contre-productives lorsqu'elles sont mal employées. L'INSEP propose donc aujourd'hui un nouvel ouvrage, essentiel pour comprendre ces différentes techniques, et qui permettra aux athlètes, à leurs entraîneurs et à leur encadrement médical de véritablement mettre en œuvre des politiques de récupération efficaces et adaptées aux spécificités de l'athlète, mais aussi à celles de son sport et de son calendrier sportif. Près de 1 650 articles scientifiques du monde entier ont ainsi été analysés et synthétisés afin d'offrir au lecteur des informations fiables, loin de l'empirisme ou des effets de mode qui ne garantissent évidemment pas toujours la réussite... Du haut de ses vingt-trois chapitres, cet ouvrage nous invite à une nouvelle orientation dans la compréhension des processus de récupération chez le sportif. En complément de cette analyse pertinente des différentes méthodes de récupération, quelques études de cas mettant le sportif au cœur du dispositif de récupération, viennent éclairer nos zones d'ombre et ainsi améliorer notre connaissance de la récupération en sport

Sotrovimab therapy elicits antiviral activities against Omicron BQ.1.1 and XBB.1.5 in sera of immunocompromised patients [letter]

International audienc