Lanthionine synthetase C-like protein 2 (LANCL2) is a member of the LANCL protein family, which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compound with insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling of ABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approaches and validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeutic potential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effects and modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. A case for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novel LANCL2 ligands such as NSC61610 against inflammatory bowel disease in mice. This dissertation discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of new classes of orally active drugs against chronic metabolic, immune-mediated and infectious diseases and as a validated target that can be used in precision medicine. Specifically, in Chapter 2 of the dissertation, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR - agonists share a binding site on the surface of LANCL2. In Chapter 3 of the dissertation, structure-based virtual screening was performed. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. In Chapter 4 of the dissertation, we developed a novel integrated approach for creating a synthetic patient population and testing the efficacy of the novel pre-clinical stage LANCL2 therapeutic for Crohn's disease in large clinical cohorts in silico. Efficacy of treatments on Crohn's disease was evaluated by analyzing predicted changes of Crohn's disease activity index (CDAI) scores and correlations with immunological variables were evaluated. The results from our placebo-controlled, randomized, Phase III in silico clinical trial at 6 weeks following the treatment shows a positive correlation between the initial disease activity score and the drop in CDAI score. This observation highlights the need for precision medicine strategies for IBD. / Ph. D.

La diversité des maladies des patients de réanimation fait que l’environnement technologique de soins intensifs est composé de nombreux systèmes de monitorage de constantes physiologiques, permettant à l’équipe soignante de déterminer un traitement adapté au patient. De plus en plus de systèmes ont une fonction d’assistance à la prescription ou aux soins afin de réduire la charge de travail et mentale des infirmières exigées par certains traitements ou protocoles. Ces systèmes informatisés facilitent l’intégration du protocole et de l’information disponible dans les signaux et peuvent aboutir à des systèmes de complexité élevée. La question de l’évaluation de la qualité de la réalisation et de la balance bénéfice/risque pour les patients liée à l’usage de nouveaux systèmes d’assistance se pose alors. Un problème consiste à mener cette évaluation a priori dès la conception du protocole ou de l’algorithme. Ce travail de thèse donne un exemple de méthode pour un système d’assistance au contrôle de la glycémie des patients de réanimation : l’évaluation est menée depuis la conception de l’algorithme de contrôle jusqu’à une étude clinique de grande ampleur. L’origine du dispositif étudié vient de ce que les patients présentent souvent une hyperglycémie liée au stress à leur arrivée en réanimation (l’augmentation de l’insulino-résistance, l’administration de certaines de drogues ou la déficience en insuline inhibent la réponse physiologique à l’augmentation de la glycémie). Un problème vient alors de ce que, d’une part, l’hyperglycémie prolongée étant associée à une morbidité voire une mortalité accrue, contrôler la glycémie est bénéfique, et d’autre part réduire la glycémie fait courir le risque d’épisodes hypoglycémiques pendant le séjour en réanimation. Dans ce cas, optimiser la balance bénéfice/risque est encore un problème ouvert. Bien qu’il existe de nombreux travaux sur la modélisation de la pharmacodynamique du système glucose-insuline, peu de travaux exploitent ces modèles pour fournir un système de contrôle fonctionnel, testé et industrialisable. La thèse présente un système de contrôle glycémique ainsi qu’une méthode d’évaluation généralisable à d’autres systèmes, qui teste numériquement les performances techniques et cliniques de ce type de systèmes sur des patients virtuels. Les résultats d’une étude clinique réelle sont aussi présentés. / The variety of ICU patients diseases implies that technological environment of critical care is composed of many vital signs monitoring systems, allowing the medical team to determine appropriate treatment to the patient. More and more systems have a decision-making support function to reduce the mental and physical workload of nurses required for certain treatments or protocols. These computerized systems facilitate the integration of the protocol and the information available in the signals and can lead to systems of high complexity. The issue of assessing the performances and the benefit/risk balance for the patient related to the use of new support systems arises. The problem is to conduct this evaluation a priori, during the design process of the protocol or algorithm. This work provides an example of a method to support the control of blood glucose in the ICU system evaluation is conducted for the design of the control algorithm to a large-scale clinical study.The origin of the studied device comes from the fact that patients often experience hyperglycemia due to stress upon their arrival in the ICU (increased insulin resistance, administration of interacting drugs or insulin deficiency inhibit the physiological response to the blood sugar increase). A problem then is that, on the one hand, as sustained hyperglycemia is associated with an increased morbidity or mortality, controlling glycaemia reduces risks, but, on the other hand, reducing blood sugar exposes to the risk of hypoglycemia during the ICU stay. In this case, optimizing benefit/risk ratio is still an open problem.Although there are many studies on modeling the pharmacodynamics of glucose-insulin system, few works use these models to provide a functional, tested and industrialized control system. The thesis presents a glycemic control system and a generalized method of evaluation with other systems, which tests digitally technical and clinical performances of such systems on virtual patients. The results of a real clinical trial are also presented.