Current Methods in Synthesis of Cyclic Oligonucleotides and Analogues

Cyclic oligonucleotides and analogues (cONs) are highly specific ligands for DNA, RNA and proteins. cONs are described in several diagnostic and therapeutic applications, as well as in elucidating enzyme mechanisms and as lead structures for development of new drugs because of their unusual chemical and biological properties in comparison with linear counterparts. In numerous structural studies it has been shown that conformational constraints imposed by circularity cause unique topologies, which in some cases can result into peculiar ON nanostructures. The wide field of applications of cONs has called for the definition of easy and efficient strategies to produce such compounds. In this review, we will describe the enzymatic and chemical approaches reported for the synthesis of cONs with a particular focus on the chemical ones. We proceed following a chronological order from the earliest to the latest methods and improvements, describing at first the natural cyclic ONs and then modified linkages and cyclic analogues.