title: Privileged Structures Meet Human T-Cell Leukemia Virus-1 (HTLV-1): C2-Symmetric 3,4-Disubstituted Pyrrolidines as Nonpeptidic HTLV-1 Protease Inhibitors.
abstract: 3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, to the best of our knowledge, the most potent nonpeptidic inhibitor of HTLV-1 PR described so far. The X-ray structures of two representatives bound to HTLV-1 PR were determined, and the structural basis of their affinity is discussed.
authors.affiliation: †Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kuhnert
authors.affiliation: †Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blum
authors.affiliation: ‡LOEWE-Zentrum für Synthetische Mikrobiologie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.affiliation: †Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany.
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D011759:Pyrrolidines; D016282:Aspartic Acid Endopeptidases; C079711:HTLV-1 protease