title: Pyrrolidinyl PNA with α/β-Dipeptide Backbone: From Development to Applications.
abstract: The specific pairing between two complementary nucleobases (A·T, C·G) according to the Watson-Crick rules is by no means unique to natural nucleic acids. During the past few decades a number of nucleic acid analogues or mimics have been developed, and peptide nucleic acid (PNA) is one of the most intriguing examples. In addition to forming hybrids with natural DNA/RNA as well as itself with high affinity and specificity, the uncharged peptide-like backbone of PNA confers several unique properties not observed in other classes of nucleic acid analogues. PNA is therefore suited to applications currently performed by conventional oligonucleotides/analogues and others potentially beyond this. In addition, PNA is also interesting in its own right as a new class of oligonucleotide mimics. Unlimited opportunities exist to modify the PNA structure, stimulating the search for new systems with improved properties or additional functionality not present in the original PNA, driving future research and applications of these in nanotechnology and beyond. Although many structural variations of PNA exist, significant improvements to date have been limited to a few constrained derivatives of the privileged N-2-aminoethylglycine PNA scaffold. In this Account, we summarize our contributions in this field: the development of a new family of conformationally constrained pyrrolidinyl PNA having a nonchimeric α/β-dipeptide backbone derived from nucleobase-modified proline and cyclic β-amino acids. The conformational constraints dictated by the pyrrolidine ring and the β-amino acid are essential requirements determining the binding efficiency, as the structure and stereochemistry of the PNA backbone significantly affect its ability to interact with DNA, RNA, and in self-pairing. The modular nature of the dipeptide backbone simplifies the synthesis and allows for rapid structural optimization. Pyrrolidinyl PNA having a (2'R,4'R)-proline/(1S,2S)-2-aminocyclopentanecarboxylic backbone (acpcPNA) binds to DNA with outstanding affinity and sequence specificity. It also binds to RNA in a highly sequence-specific fashion, albeit with lower affinity than to DNA. Additional characteristics include exclusive antiparallel/parallel selectivity and a low tendency for self-hybridization. Modification of the nucleobase or backbone allowing site-specific incorporation of labels and other functions to acpcPNA via click and other conjugation chemistries is possible, generating functional PNAs that are suitable for various applications. DNA sensing and biological applications of acpcPNA have been demonstrated, but these are still in their infancy and the full potential of pyrrolidinyl PNA is yet to be realized. With properties competitive with, and in some aspects superior to, the best PNA technology available to date, pyrrolidinyl PNA offers great promise as a platform system for future elaboration for the fabrication of new functional materials, nanodevices, and next-generation analytical tools.
authors.affiliation: Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand.
authors.forename: Tirayut
authors.initials: T
authors.lastname: Vilaivan
mesh_terms: D004247:DNA / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D036103:Nanotechnology; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D012313:RNA / Q000737:chemistry
chemical_list: D004151:Dipeptides; D020135:Peptide Nucleic Acids; D011759:Pyrrolidines; D012313:RNA; D004247:DNA