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APPLICATIONS OF PEPTIDES NUCLEIC ACIDS (PNA) IN MOLECULAR MEDICINE AND BIOTECHNOLOGY
Minerva Biotecnologica 1999 September;11(3):193-203
Copyright © 1999 EDIZIONI MINERVA MEDICA
lingua: Inglese
New trends in molecular pharmacology: artificial modulation of gene expression by transcription modifiers
Piva R. 1, Gambari R. 2
1 Department of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy; 2 Biotechnology Centre, Ferrara University, Ferrara, Italy
Synthetic oligonucleotides have recently been the object of many investigations aimed to develop sequence-selective compounds able to modulate, either positively or negatively, transcription of eukaryotic and viral genes. This issue is of great interest in order to design anti-tumor compounds and anti-viral agents, as well as compounds able to induce cellular differentiation. Alteration of gene expression using transcription modifiers has been reported using DNA-binding drugs, such as distamycin, chromomycin, mithramycin, actinomycin D and CC-1065. In this review we describe recent reports on the use of (a) triple-helix forming oligonucleotides, (b) decoy molecules (either DNA or RNA) and (c) peptide nucleic acids for artificial modulation of gene expression. Triplex forming oligonucleotides recognizing promoter regions of eukaryotic and viral genes are able to inhibit the interaction between transcription factors and target DNA thereby altering transcription (anti-gene strategy). In addition, triplex forming oligonucleotides recognizing regions located 3’ of the transcription initiation site are able to inhibit the progression of RNA polymerase. These effects could be enhanced by the use of DNA-binding drugs recognizing the triple helix. Alteration of gene expression has been reported in the case of the c-myc, HER-2/neu, c-erbB, Ha-ras, c-fos, IGF-I genes by using triple helix forming oligonucleotides directed in most cases against promoter sequences. On the other hand, alteration of transcription could be obtained by using synthetic oligonucleotides mimicking target sites of transcription factors (the decoy approach). This could lead to either inhibition or activation of gene expression, depending on the biological functions of the target transcription factors. In this report we describe effects of this approach by using decoy molecules against a variety of transcription factors, including E2F, Ets, NF-kB, CRE binding protein. Finally, modulation of gene transcription by using peptide nucleic acids is discussed as a possible approach to design new anti-cancer and anti-viral drugs.