Inhibitors of Cyclic Dinucleotide Phosphodiesterases and Cyclic Oligonucleotide Ring Nucleases as Potential Drugs for Various Diseases  
[PERSON]  
1 Chemistry Department, Purdue University, West Lafayette, IN 47907, USA; [PERSON]DDRESS] (C.S.V. ); [PERSON]ADDRESS] (S.M.O.) [PERSON]  
1 Chemistry Department, Purdue University, West Lafayette, IN 47907, USA; [PERSON]DDRESS] (C.S.V. ); [PERSON]ADDRESS] (S.M.O.) [PERSON]  
2 Department of Chemistry and Biochemistry, University of Not  
cardiovascular [5; 6] and other diseases. This review is focused on cyclic di- and oligonucleotides, but those interested in inhibitors of cyclic mononucleotide PDEs are directed to some recent reviews on cAMP and cGMP PDEs [7; 8; 9]. In the late 1980s, [PERSON] published a series of papers that revealed the structure and function of c-di-GMP, an archetypical cyclic dinucleotide (CDN) [10; 11]. Since [PERSON]'s original work, other types of cyclic dinucleotides with 3\({}^{\prime}\)-5\({}^{\prime}\) phosphodieser linkages (for example c-di-AMP, cGAMP) were discovered in bacteria. In bacteria, the role of cyclic oligonucleotides (cONs) as second messenger molecules has been rapidly expanding since their discovery [10; 11; 12]. In higher organisms, cyclic dinucleotides that contain a non-canonical 2\({}^{\prime}\)3\({}^{\prime}\)-phosphodiester linkage have been described [13; 14; 15; 16]. In humans, the inflammatory response caused by CDNs has been gaining attention over the last decade as specific druggable targets have emerged [17]. A timeline of cON discovery is shown in Figure 1. For the purpose of this review, CDNs will also be classified as cONs. The biologically relevant cONs described thus far have between 2 and 6 nucleobases. Since cONs are signal activators, the concentrations of these second messenger molecules are highly regulated in cells. cONs are enzymatically synthesized from nucleotide triphosphates (NTPs) by cyclases, degraded by phosphodiesterase to linear oligonucleotides and then further degraded into nucleotide monophosphates (NMPs) (Figure 2). Interestingly, some isoforms of PDEs can hydrolyze cONs all the way to NMPs, whereas other isoforms are only able to cleave one phosphodieser bond. Isoforms of PDEs that only cleave one phosphodieser bond require the aid of other hydrolase enzymes to further process the linear oligonucleotides to NMPs. Specifically, oligoribonuclease (Orn) and other nano-RNase (NrnA) enzymes are responsible for this process. Although there are both linear [25] and cyclic nucleotide phosphates (CNPs) that operate as signaling molecules, the cyclic nucleotides are much more diverse in their isomerism and function. 3\({}^{\prime}\),5\({}^{\prime}\)-cAMP and 3\({}^{\prime}\),5\({}^{\prime}\)-cGMP are among the most widely studied, as these two CNPs are responsible for smooth muscle relaxation, bronchodilation, and vasodilation in humans [26; 27; 28]. In bacteria, 3\({}^{\prime}\),5\({}^{\prime}\)-cAMP and 3\({}^{\prime}\),5\({}^{\prime}\)-cGMP have been linked to a myriad of processes through gene expression regulation [12; 29]. In addition to the canonical 3\({}^{\prime}\)-5\({}^{\prime}\) phosphate linkage, 2\({}^{\prime}\)3\({}^{\prime}\)-CNPs have also recently been found to bind to bacterial ribosomes, inhibiting gene expression at a translational level [30; 31]. The dinucleotides are even more complex than their mononucleotide counterparts, as the nucleotide bases may either be homologous or heterologous in addition to utilizing various linkage patterns (Figure 3). The current understanding is that bacteria most commonly produce cONs with a 3\({}^{\prime}\),3\({}^{\prime}\)-linkage (c-di-AMP, c-di-GMP, cUAMP, cGAMP, cGAAMP, cA\({}_{4}\), and cA\({}_{6}\)) (Figure 2A) whereas eukaryotic cells produce 2\({}^{\prime}\),3\({}^{\prime}\)-cGAMP. However, eukaryotic cells are not always present in the 3\({}^{\prime}\)-cGAMP. Figure 2: (**A**) Bacterial cON signaling overview showing the synthesis (cyclase) and degradation (PDE) of bacterial cONs.