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.