title: Hitting a Moving Target: How Does an N-Methyl Group Impact Biological Activity?
abstract: Macrocycles have several advantages over small-molecule drugs when it comes to addressing specific protein-protein interactions as therapeutic targets. Herein we report the synthesis of seven new cyclic peptide molecules and their biological activity. These macrocycles were designed to understand how moving an N-methyl moiety around the peptide backbone impacts biological activity. Because the lead non-methylated structure inhibits the oncogenic regulator heat-shock protein 90 (Hsp90), two of the most potent analogues were evaluated for their Hsp90 inhibitory activity. We show that incorporating an N-methyl moiety controls the conformation of the macrocycle, which dramatically impacts cytotoxicity and binding affinity for Hsp90. Thus, the placement of an N-methylated amino acid within a macrocycle generates an unpredictable change to the compound's conformation and hence biological activity.
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Yen Chin
authors.initials: YC
authors.lastname: Koay
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Richardson
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Samantha S
authors.initials: SS
authors.lastname: Zaiter
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kho
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Sheena Y
authors.initials: SY
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Tran
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Ka Wai
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Buckton
authors.affiliation: Department of Chemistry, University of New South Wales, Gate 2 High Street, Dalton F12, Sydney, NSW, 2008, Australia. s.mcalpine@unsw.edu.au.
authors.forename: Shelli R
authors.initials: SR
authors.lastname: McAlpine
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008745:Methylation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010456:Peptides, Cyclic; D054852:Small Molecule Libraries
keywords: antitumor agents; cytotoxicity; heat-shock protein 90; protein folding; unfolded protein response