Systematic alanine-scanning of the linear peptide bisebromoamide (BBA), isolated from a marine cyanobacterium, is enabled by targeting the solid phase peptide synthesis of thiazole analogues. The synthetic Tz-BBA analogues have comparable cytotoxicity (nM) to bisebromoamide and cellular morphology assays indicate that they target the actin cytoskeleton. Pathway inhibition in human colon tumour (HCT-116) cells has been explored using reverse phase protein array (RPPA) analysis, which shows a dose-dependent response of 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.
Johnston, Heather; Boys, Sarah; Makda, Ashraff; Carragher, Neil; Hulme, Alison. (2016). Naturally Inspired Peptide Leads: Alanine Scanning Reveals an Actin-Targeting Thiazole Analogue of Bisebromoamide, [dataset]. University of Edinburgh. School of Chemistry.. http://dx.doi.org/10.7488/ds/1417.