ISSN:
1573-3904
Keywords:
Peptide drug
;
Peptide delivery
;
Leucine zipper
;
Anticancer drugs
;
Transcription factors
;
Jun
;
Fos
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Various members of the bZip and bHLH-Zip families of eukaryotic transcription factors,including Jun, Fos, and Myc, have been identified as oncoproteins; mutation or deregulatedexpression of these proteins leads to certain types of cancer. These proteins can only bind totheir cognate DNA enhancer sites following homodimerization, or heterodimerization withanother family member, via their leucine zipper domain. Thus, a novel anticancer strategywould be to inhibit dimerization of these proteins, thereby blocking their DNA binding andtransactivation functions. In this paper we show that it is possible to rationally design leucinezipper peptides that bind with high affinity to the leucine zipper dimerization domains of c-Jun and c-Fos, thus preventing the formation of functional c-Jun homodimers and c-Jun:c-Fosheterodimers; we refer to such peptides as superzippers (SZs). In vivo, c-Jun:SZ and c-Fos:SZheterodimers should be nonfunctional as they lack one of the two basic domains that areessential for DNA binding. While the transport of a peptidic agent into cells often poses asevere obstacle to its therapeutic use, we show that a 46-residue leucine zipper peptide canbe transported into HeLa cells by coupling it to a 17-residue carrier peptide from theAntennapedia homeodomain, thus paving the way for detailed studies of the therapeuticpotential of superzipper peptides.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008883300477
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