Conformational features of peptidic nucleic acids for the rational design of biologically active PNAs and hybrids PNA-oligonucleotides

The ­search for new oli­go­nu­cleo­tides ­with ­improved prop­er­ties rep­re­sents an impor­tant ­step for the devel­op­ment of oli­go­nu­cleo­tides as pow­erful bio­mo­lec­ular ­tools, anti­sense and antigene ­agents, molec­ular ­probes and bio­sen­sors. One of the ­most inter­esting of the new deriv­a­tives is Pep­tide ­Nucleic ­Acid (PNA), an ana­logue of DNA in ­which the back­bone is a pseu­do­pep­tide ­rather ­than a ­sugar. PNA ­mimics the beha­viour of DNA and ­binds com­ple­men­tary ­nucleic ­acid ­strands, ­with ­higher ­affinity and spec­i­ficity ­than cor­re­sponding oli­go­nu­cleo­tides. The ­unique prop­er­ties of PNA ­open up ­novel molec­ular ­biology and bio­chem­istry appli­ca­tions ­that are unachiev­able ­with tra­di­tional oli­go­nu­cleo­tides and pep­tides. The non-­charged ­nature of the PNA back­bone is an impor­tant fea­ture ­leading to ­higher ­thermal ­stability of PNA/DNA ­duplexes com­pared to DNA/DNA ­duplexes and ­stability of PNA ­duplexes ­with DNA inde­pen­dent of ­salt con­cen­tra­tion. PNA oli­gomers are ­resistant to deg­ra­da­tion by ­enzymes, and the life­time of ­these com­pounds is ­extended ­both in ­vivo and in ­vitro. The direc­tion of ­rational ­drug ­design of new PNA ­with spe­cific func­tions ­depends crit­i­cally on under­standing the ­basic prin­ci­ples of spec­i­ficity of bio­mo­lec­ular rec­og­ni­tion for ­this ­class of mole­cules. ­Thus, the com­par­a­tive anal­ysis of con­for­ma­tional ­data on PNA/PNA, PNA/RNA, PNA/DNA ­duplexes and PNA2/DNA ­triplex rep­re­sents the ­starting ­point for the ­design of new ­PNAs. In addi­tion, the inves­ti­ga­tion of mod­i­fied ­PNAs and PNA/DNA chi­meras may pro­vide a new gen­er­a­tion of ­nucleic ­acid ­mimetics ­with ­large-­scale appli­ca­tion in bio­log­ical ­systems.