tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening酪氨酸激酶麦克米兰non-enzymatic抑制剂和潜在的抗过敏药物类化合物发现的虚拟和体外筛选.pdfVIP

Tyrosine Kinase Syk Non-Enzymatic Inhibitors and Potential Anti-Allergic Drug-Like Compounds Discovered by Virtual and In Vitro Screening 1 1 1 2,3,4,5,6 1 Bruno O. Villoutreix , Guillaume Laconde , David Lagorce , Pierre Martineau , Maria A. Miteva , Piona Dariavach2,3,4,5,6* ´ ´ 1 INSERM, U973, (MTi Unit), Universite Paris Diderot, Paris, France, 2 IRCM, Institut de Recherche en Cancerologie de Montpellier, Montpellier, France, 3 INSERM, U896, ´ ´ Montpellier, France, 4 Universite Montpellier1, Montpellier, France, 5 Universite Montpellier2, Montpellier, France, 6 CRLC Val d’Aurelle Paul Lamarque, Montpellier, France Abstract In the past decade, the spleen tyrosine kinase (Syk) has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibo