title: Synthesis and biological evaluation of analogues of the potent ADAM8 inhibitor cyclo(RLsKDK) for the treatment of inflammatory diseases and cancer metastasis.
abstract: The metalloproteinase ADAM8 serves as a pivotal catalyst in the development of inflammatory diseases and cancer metastasis. The cyclic peptide cyclo(RLsKDK) has been shown to inhibit the enzymatic activity of ADAM8 with high specificity and potency. Herein we report a structure-activity relationship (SAR) study of cyclo(RLsKDK) that involves the synthesis and biological evaluation of the lead compound and structural analogues thereof. This study provides insight into the ligand-receptor interactions that govern the binding of cyclo(RLsKDK) to the ADAM8 disintegrin domain and represents a stepping stone for the development of new treatments for inflammatory diseases and cancer metastasis.
authors.affiliation: School of Biological Sciences and The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3a Symonds St, Auckland Central 1010, New Zealand.
authors.forename: Victor
authors.initials: V
authors.lastname: Yim
authors.affiliation: School of Biological Sciences and The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3a Symonds St, Auckland Central 1010, New Zealand.
authors.forename: Anaïs F M
authors.initials: AFM
authors.lastname: Noisier
authors.affiliation: School of Biological Sciences and The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3a Symonds St, Auckland Central 1010, New Zealand.
authors.forename: Kuo-Yuan
authors.initials: KY
authors.lastname: Hung
authors.affiliation: Department of Neurosurgery, Marburg University, University Hospital, Baldingerstr., 35053 Marburg, Germany.
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Bartsch
authors.affiliation: Department of Neurosurgery, Marburg University, University Hospital, Baldingerstr., 35053 Marburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlomann
authors.affiliation: School of Biological Sciences and The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3a Symonds St, Auckland Central 1010, New Zealand; School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland 1010, New Zealand. Electronic address: m.brimble@auckland.ac.nz.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000276:immunology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D051722:ADAM Proteins; C068490:ADAM8 protein, human
keywords: ADAM8 inhibitors; Cancer metastasis; Cyclic peptides; Peptidomimetics; SAR study