Inhibitors of Cyclic Dinucleotide Phosphodiesterases and Cyclic Oligonucleotide Ring Nucleases as Potential Drugs for Various Diseases.

Abstract

The phosphodiester linkage is found in DNA, RNA and many signaling molecules, such as cyclic mononucleotide, cyclic dinucleotides (CDNs) and cyclic oligonucleotides (cONs). Enzymes that cleave the phosphodiester linkage (nucleases and phosphodiesterases) play important roles in cell persistence and fitness and have therefore become targets for various diseased states. While various inhibitors have been developed for nucleases and cyclic mononucleotide phosphodiesterases, and some have become clinical successes, there is a paucity of inhibitors of the recently discovered phosphodiesterases or ring nucleases that cleave CDNs and cONs. Inhibitors of bacterial c-di-GMP or c-di-AMP phosphodiesterases have the potential to be used as anti-virulence compounds, while compounds that inhibit the degradation of 3',3'-cGAMP, cA₃, cA₄, cA₆ could serve as antibiotic adjuvants as the accumulation of these second messengers leads to bacterial abortive infection. In humans, 2'3'-cGAMP plays critical roles in antiviral and antitumor responses. ENPP1 (the 2'3'-cGAMP phosphodiesterase) or virally encoded cyclic dinucleotide phosphodiesterases, such as poxin, however, blunt this response. Inhibitors of ENPP1 or poxin-like enzymes have the potential to be used as anticancer and antiviral agents, respectively. This review summarizes efforts made towards the discovery and development of compounds that inhibit CDN phosphodiesterases and cON ring nucleases.