Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated.Starting from fifteen structurally diverse natural products,a focused library featured by Michael acceptors is constructed with IBX mediated oxidation.Biological assay on five tumor cell lines indicates that four Michael acceptors,8a,11a,12a,14a,are with improved cytotoxicity(3-10 folds more potent than the parent compounds),which merit further investigations.Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor.The results suggest that the strategy is not only effective and relatively high discovery rate(28%),but also resource saving.

Precise assembly of inside-out cell membrane camouflaged nanoparticles via bioorthogonal reactions for improving drug leads capturing

Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function.However,random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites,especially when applied to intracellular regions of transmembrane proteins.Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem.Herein,inside-out cell membrane camouflaged magnetic nanoparticles(IOCMMNPs)were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2.Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe_(3)O_(4)nanoparticles to prepare IOCMMNPs.The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay.Ultimately,two compounds,senkyunolide A and ligustilidel,were successfully captured,and their potential antiproliferative activities were further testified by pharmacological experiments.It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.

Recent progress in fragment-based drug discovery facilitated by NMR spectroscopy

Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.

The 2016 Lasker-DeBakey Clinical Medical Research Award: Innovative hepatitis C virus(HCV) replicons leading to drug development for hepatitis C cure

The 2016 Lasker-DeBakey Clinical Medical Research Award was given to three scientists working on different stages of the translational sciences on bringing a high efficacious therapy against hepatitis C virus （HCV） infection to a reality. An effective treatment of HCV chronic infection was developed, by a team led by Michael Sofia, using a prodrug approach and the drug PSI-7977 or Sofosbuvir was approved in 2013 less than 28 years after the initial discovery of HCV.