Modifications of Peptide Nucleic Acid(PNA)monomers as a strategy for modulating the physicochemical and pharmacokinetic properties of PNA oligomers

摘要

Tinkering with the flow of genetic information via sequence selective binding of synthetic oligonucleotides to DNA,RNA or nucleic acid-binding proteins(e.g.polymerase or helicase enzymes and transcription factors),has been an area of intense research activities in biomedical sciences.The underlying mechanism of gene silencing,or over-expression,by means of a synthetic compound is conceptually simple and relies on the rational,structure-based design of molecules that can mimic the function of natural oligonucleotides.In principal,the successful design of such molecules should provide therapeutic agents and biomedical tools which are capable of selectively modulating the flow of genetic information,at either the translation or the transcription level.In spite of great progress made towards achieving these goals,the simplicity of the underlying principle belies many yet unanswered secrets that are utilized by nature to properly choreograph gene expression.Recently,a number of review articles have highlighted the key innovations in the field of oligonucleotide(ODN)and peptide nucleic acid(PNA)chemistry,as well as applications of their oligomers in antisense/antigene technologies,diagnostics and drug discovery efforts1'2.The focus of this article is to briefly review the key obstacles hampering progress,and summarize some recent innovative approaches addressing some of the problems.The emphasis of the article is on the contributions of peptide chemistry to the field,as it pertains to the synthesis of novel PNA oligomers with modified physicochemical properties.