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.