title: Linker-Region Modified Derivatives of the Deoxyhypusine Synthase Inhibitor CNI-1493 Suppress HIV-1 Replication.
abstract: The inhibition of cellular factors that are involved in viral replication may be an important alternative to the commonly used strategy of targeting viral enzymes. The guanylhydrazone CNI-1493, a potent inhibitor of the deoxyhypusine synthase (DHS), prevents the activation of the cellular factor eIF-5A and thereby suppresses HIV replication and a number of other diseases. Here, we report on the design, synthesis and biological evaluation of a series of CNI-1493 analogues. The sebacoyl linker in CNI-1493 was replaced by different alkyl or aryl dicarboxylic acids. Most of the tested derivatives suppress HIV-1 replication efficiently in a dose-dependent manner without showing toxic side effects. The unexpected antiviral activity of the rigid derivatives point to a second binding mode as previously assumed for CNI-1493. Moreover, the chemical stability of CNI-1493 was analysed, showing a successive hydrolysis of the imino bonds. By molecular dynamics simulations, the behaviour of the parent CNI-1493 in solution and its interactions with DHS were investigated.
authors.affiliation: Institute of Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Hamburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schröder
authors.affiliation: ZBH Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Kolodzik
authors.affiliation: ZBH Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.affiliation: Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Krepstakies
authors.affiliation: Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Poornima
authors.initials: P
authors.lastname: Priyadarshini
authors.affiliation: Department of Medicine, Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Hartjen
authors.affiliation: Department of Medicine, Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: van Lunzen
authors.affiliation: ZBH Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rarey
authors.affiliation: Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.affiliation: Institute of Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006868:Hydrolysis; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship; D014779:Virus Replication; D000813:Anilides; D006146:Guanidines
chemical_list: D019380:Anti-HIV Agents; D006835:Hydrazones; D006899:Mixed Function Oxygenases; C097256:semapimod; D000813:Anilides; D006146:Guanidines; C047991:deoxyhypusine hydroxylase
keywords: Anti-HIV activity; DHS; Deoxyhypusine synthase; Inhibitor synthesis; eIF-5A