Screening of a combinatorial library of synthetic polyamines displaying selectivity in multiple ion-pairing interactions with model polyanionic compounds in aqueous organic solutions.
The biological activity of natural polyamines is due in large part to their ability to form ion-pairing interactions with polyanionic biomolecules, such as proteins, oligonucleotides, and sulfated oligosaccharides. Unfortunately, the diversity of biogenic polyamines is compromised by their limitation to only just a few internitrogen spacers. As a proof-of-principle study, a synthetic split-pool library of linear triamines was screened in an on-bead assay against a selection of model trisulfonated azo dyes (1, 2, and 3) and a short glutamate-rich nonameric peptide (4) to demonstrate its use in the discovery of selective ligands via multivalent ion pairing. From screening a 196-membered split-pool library against the dyes in aqueous organic solutions, with or without spermidine as competing ligand, it was found that the most frequent residues possessed internitrogen distances that were very similar to the sulfonate distances on the dyes. The results from these screening assays were used in the design of two polyamine sequences (8, 8Aoc(R)-8Aoc(R), and 12, 2Acc(R)-epsilonAhx(R)) for follow-up studies in solution phase. These triamines demonstrated the same selectively toward dyes 2 and 3 as observed by the solid-phase approach. In addition, resin-supported triamines, synthesized as discrete compounds, were able to selectively extract either dye 2 or 3 from a mixture of the two, further verifying the observations made from the library screening efforts. With peptide 4, containing three glutamate residues, a preference was found for rather long residues (12 and 8 carbons long), which is suggestive of a linear peptide, rather than a helical motif under the conditions of the screening.
Manku
Sukhdev
S
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Hall
Dennis G
DG
D001391:Azo Compounds / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D008024:Ligands; D008956:Models, Chemical; D009841:Oligonucleotides / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis; D011073:Polyamines / Q000138:chemical synthesis*; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry; D012117:Resins, Synthetic / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013431:Sulfates / Q000737:chemistry; D014867:Water / Q000737:chemistry
D001391:Azo Compounds; D008024:Ligands; D009841:Oligonucleotides; D019151:Peptide Library; D010455:Peptides; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; D011506:Proteins; D012117:Resins, Synthetic; D012996:Solutions; D013431:Sulfates; D014867:Water