Eukaryotic transcriptional activators are minimally comprised of a DNA bind
ing domain and a separable activation domain; most activator proteins also
bear a dimerization module. We have replaced these protein modules with syn
thetic counterparts to create artificial transcription factors. One of thes
e, at 4.2 kDa, mediates high levels of DNA site-specific transcriptional ac
tivation in vitro. This molecule contains a sequence-specific DNA binding p
olyamide in place of the typical DNA binding region and a nonprotein linker
in place of the usual dimerization peptide. Thus our activating region, a
designed peptide, functions outside of the archetypal protein context, as l
ong as it is tethered to DNA, Because synthetic polyamides can, in principl
e, be designed to recognize any specific sequence, these results represent
a key step toward the design of small molecules that can up-regulate any sp
ecified gene.