title: The design and implementation of a generic lipopeptide scanning platform to enable the identification of 'locally acting' agonists for the apelin receptor.
abstract: This Letter describes methodology to enable the identification of tool or therapeutic lipopeptides which modulate the function of membrane bound proteins. The choice of lipopeptides as a chemotype is the amalgamation of multiple medicinal chemistry considerations including duration of action, low systemic exposure and access to intracellular components. The 'lipopeptide shuffle' has been applied here to the APJ receptor and has rapidly resulted in the discovery of a 33 nM APJ agonist hit from an initial 369 member lipopeptide synthetic array.
authors.affiliation: Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK. Electronic address: stevemck1@btinternet.com.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: McKeown
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Zecri
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Fortier
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Taggart
authors.affiliation: Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
authors.forename: Lilya
authors.initials: L
authors.lastname: Sviridenko
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: McAllister
authors.affiliation: Novartis Institutes for BioMedical Research, Technology Square, Cambridge, MA 02139, USA.
authors.forename: Sokhom S
authors.initials: SS
authors.lastname: Pin
mesh_terms: D000075244:Apelin Receptors; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D055666:Lipopeptides; D043562:Receptors, G-Protein-Coupled
keywords: APJ agonist; Apelin; Lipopeptide; Pepducin; Peptide; Protein protein interactions