Pierre Evenou

L’utilisation de siRNA est une nouvelle approche thérapeutique très prometteuse. Néanmoins leur transfection à visée thérapeutique est un réel défi. Les obstacles à franchir pour élaborer des agents de transfection sûrs et fiables sont nombreux. Afin de les contourner nous nous sommes attachés à la construction d’un système dynamique qui, à l’image des virus, est constitué de briques moléculaires, s’emboitant et interagissant avec des acides nucléiques selon des interactions supramoléculaires. Ainsi, nous avons élaboré des polymères supramoléculaires polycationiques à base de monomères de cyclodextrines pontées, fonctionnalisées par un groupement adamantyle. Ce type de conjugué pallie un problème manifeste dans la littérature concernant les assemblages de β-CD souvent insolubles ou bien auto-inclus. L’ajout éventuel d’une autre fonction cationique pour améliorer l’interaction avec les siRNA a aussi été réalisé. Ainsi, la capacité à s’auto-assembler de quatre composés a été étudiée par RMN-1H, RMN-ROESY, ITC, RMN-DOSY, et SANS. Par ailleurs, ces composés ont montré une certaine capacité à complexer et à protéger les siRNA. L’un de ces composés a de plus montré une bonne aptitude à transfecter des siRNA in vitro, sans induire de toxicité. Les assemblages CD-siRNA ont finalement été observés par cryo-TEM et ont montré la formation de fibres, organisées de manière hiérarchique et hautement coopérative. Nous avons ainsi créé des assemblages supramoléculaires uniques à base d’acides nucléiques, rappelant la structure, la taille et la fonction d’un virus.

Introduction The EF-BI study, a nationwide observational and retrospective study conducted in France, found better insulin persistence, fewer insulin therapy-related acute hospitalizations, and lower healthcare costs in adults with Type 2 diabetes (T2D) who initiated treatment with insulin glargine 300 U/mL (Gla-300) compared to those who started on insulin glargine 100 U/mL (Gla-100) over a 3-year follow-up period. Given the heterogeneity of the T2D population, the benefits observed may vary according to individuals’ characteristics. A post hoc analysis of this study was conducted to verify whether these findings were consistent in all age groups, including the elderly population. Methods Using the French national health insurance information system, adults with T2D who initiated basal insulin therapy with Gla-300 or Gla-100 between January 1, 2016, and December 31, 2020, and had no prior insulin use in the previous 6 months, were selected. Covariate adjustment using a propensity score based on key individuals’ characteristics was applied to estimate outcomes and costs between the two basal insulins. Analyses were conducted using several age cut-offs (65, 75, and 80 years). Results Overall, 235,894 people with T2D were included: 175,537 initiated treatments with Gla-100 and 60,357 with Gla-300. Across both age groups (< 65 years or older), treatment with Gla-300 was associated with better persistence and a lower frequency of acute insulin-related events. Cost comparisons per individual treated over 3 years showed significant results favoring Gla-300:— €2,031 (− 7.3%, p < 0.0001) in the < 65 years group, and— €2,914 (− 7%, p < 0.0001) in the older group. Conclusion This EF-BI post hoc analysis found that Gla-300 was associated with lower overall costs, better persistence, and fewer insulin-related acute events compared to Gla-100 in several age subgroups in people with T2D in France. Further investigations are needed to confirm these results, including glycemic control and comparison with other second-generation basal insulins

A functionnalized cyclodextrin can self-co-assemble with ds-DNA to form fibres of well-defined architecture. We have also determined the molecular structure of this abiotic assembly using cryo-EM and 3D image reconstruction.

To imitate Nature's ability to form cooperative self‐assemblies using entirely artificial molecular tools and to confer them with properties is still a true challenge. Here we show that cyclodextrins bridged with an ammonium linker which bears a hydrophobic substituent efficiently form supramolecular polymers at millimolar concentrations, avoiding the competing self‐inclusion and head‐to‐head processes. Notably, such assembly can occur at micromolecular concentrations in the presence of genomic DNA, resulting in efficient DNA compaction that is reversible upon addition of a competitive guest, and demonstrating their highly cooperative interaction. We finally show that the supramolecular polymer also cooperatively interacts with siRNA and allows its transfection.

A series of (imidazo[1,2-a]pyrazin-6-yl)ureas were synthesized through 6-aminoimidazo[1,2-a]pyrazine as a key intermediate. 1-(Imidazo[1,2-a]pyrazin-6-yl)-3-(4-methoxy - phenyl)urea displayed a cytostatic activity against a non-small cell lung cancer cell line and was chosen for further mechanistic studies. Growth kinetics highlighted a selective dose-dependent response of P53-mutant NSCLC-N6-L16 cell line and overexpression of TP53 gene induced by this compound. These pharmacological data suggest a promising reactivation of p53 mutant in NSCLC-N6-L16 cell line.