title: Inhibition of major-groove-binding proteins by pyrrole-imidazole polyamides with an Arg-Pro-Arg positive patch.
abstract: BACKGROUND
  Gene-specific targeting of any protein-DNA complex by small molecules is a challenging goal at the interface of chemistry and biology. Polyamides containing N-methylimidazole and N-methylpyrrole amino acids are synthetic ligands that have an affinity and specificity for DNA comparable to many naturally occurring DNA-binding proteins. It has been shown that an eight-ring hairpin polyamide targeted to a specific minor-groove contact within a transcription factor binding site can inhibit protein-DNA binding and gene transcription. Polyamides and certain major-groove-binding proteins have been found to co-occupy the DNA helix, however. To expand the number of genes that can be targeted by pyrrole/imidazole polyamides, we set out to develop a class of polyamides that can selectively inhibit major-groove-binding proteins.
  
  
  RESULTS
  An eight-ring hairpin polyamide conjugated to a carboxy-terminal Arg-Pro-Arg tripeptide was designed to deliver a positive residue to the DNA backbone and interfere with protein-phosphate contacts. Gel mobility shift analysis demonstrated that a polyamide hairpin-Arg-Pro-Arg binding in the minor groove selectively inhibits binding of the transcription factor GCN4 (222-281) in the adjacent major groove. Substitution within the Arg-Pro-Arg revealed that each residue was required for optimal GCN4 inhibition.
  
  
  CONCLUSIONS
  A pyrrole-imidazole polyamide that binds to a predetermined site in the DNA minor groove and delivers a positive patch to the DNA backbone can selectively inhibit a DNA-binding protein that recognizes the adjacent major groove. A subtle alteration of the DNA microenvironment targeted to a precise location within a specific DNA sequence could achieve both gene-specific and protein-specific targeting.
authors.affiliation: Arnold and Mabel Beckman Laboratory of Chemical Synthesis, California Institute of Technology, Pasadena 91125, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Bremer
authors.forename: E E
authors.initials: EE
authors.lastname: Baird
authors.forename: P B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D009757:Nylons / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins; D012492:Salts
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D007093:Imidazoles; D008024:Ligands; D009757:Nylons; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D029701:Saccharomyces cerevisiae Proteins; D012492:Salts; D011494:Protein Kinases; C096654:N-methylpyrrole; C018100:1-methylimidazole