title: Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors.
abstract: HIV protease is a well-established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of the most studied and best characterized proteins. Although the protease exhibits high flexibility, all approved drugs target virtually the same protein conformation. The development of viral cross-resistance demands the generation of inhibitors with novel scaffolds and deviating modes of binding. Herein we report the design and the short, high-yielding stereoselective synthesis of a series of chiral, symmetric pyrrolidine-based inhibitors targeting the open-flap conformation of the protease. The obtained co-crystal structure with one derivative provides a valuable starting point for further inhibitor design.
authors: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors: Jark
authors: J
authors: Böttcher
authors: Andreas
authors: A
authors: Blum
authors: Stefanie
authors: S
authors: Dörr
authors: Andreas
authors: A
authors: Heine
authors: Wibke E
authors: WE
authors: Diederich
authors: Gerhard
authors: G
authors: Klebe
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D003625:Data Collection; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D011759:Pyrrolidines; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1