Naturally Inspired Peptide Leads: Alanine Scanning Reveals an Actin-Targeting Thiazole Analogue of Bisebromoamide.
Systematic alanine scanning of the linear peptide bisebromoamide (BBA), isolated from a marine cyanobacterium, was enabled by solid-phase peptide synthesis of thiazole analogues. The analogues have comparable cytotoxicity (nanomolar) to that of BBA, and cellular morphology assays indicated that they target the actin cytoskeleton. Pathway inhibition in human colon tumour (HCT116) cells was explored by reverse phase protein array (RPPA) analysis, which showed a dose-dependent response in IRS-1 expression. Alanine scanning reveals a structural dependence to the cytotoxicity, actin targeting and pathway inhibition, and allows a new readily synthesised lead to be proposed.
EaStCHEM School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK.
Heather J
HJ
Johnston
EaStCHEM School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK.
Sarah K
SK
Boys
Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK.
Ashraff
A
Makda
Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, UK.
Neil O
NO
Carragher
EaStCHEM School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK. alison.hulme@ed.ac.uk.
Alison N
AN
Hulme
D000199:Actins / Q000378:metabolism*; D000409:Alanine / Q000032:analysis*; D002470:Cell Survival / Q000187:drug effects; D000458:Cyanobacteria / Q000737:chemistry; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
D000199:Actins; D009842:Oligopeptides; D010455:Peptides; D013844:Thiazoles; C545819:bisebromoamide; D000409:Alanine
alanine scan; cell morphology; nonribosomal peptides; reverse phase protein array; solid-phase synthesis; structure-activity relationships