Cyclic Nucleotide (cNMP) Analogues: Past, Present and Future

Abstract

Cyclic nucleotides are important second messengers involved in cellular events, and analogues of this type of molecules are promising drug candidates. Some cyclic nucleotide analogues have become standard tools for the investigation of biochemical and physiological signal transduction pathways, such as the Rp-diastereomers of adenosine and guanosine 3',5'-cyclic monophosphorothioate, which are competitive inhibitors of cAMP- and cGMP-dependent protein kinases. Next generation analogues exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity, or are caged or photoactivatable for fast and/or targeted cellular imaging. Novel specific nucleotide analogues activating or inhibiting cyclic nucleotide-dependent ion channels, EPAC/GEF proteins, and bacterial target molecules have been developed, opening new avenues for basic and applied research. This review provides an overview of the current state of the field, what can be expected in the future and some practical considerations for the use of cyclic nucleotide analogues in biological systems.

Keywords: 2′,3′-cGAMP; cAMP; cGMP; cyclic nucleotide analogues; cyclic nucleotide binding proteins.

Figure 1

Selected structures of cyclic nucleotides (1) cAMP (Adenosine-3′,5′-cyclic monophosphate syn-conformation), (2) cGMP (Guanosine-3′,5′-cyclic monophosphate), (3) Rp-cAMPS (Adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer; PKA antagonist), (4) Sp-cAMPS (Adenosine-3′,5′-cyclic monophosphorothioate, Sp-isomer; PKA agonist), (5) 8-pCPT-2′-O-Me-cAMP (8-(4-Chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate; EPAC activator), (6) cGAMP(2′-5′)/2′3′-cGAMP/2′,5′-3′,5′-cGAMP (Cyclic (guanosine-(2′ − 5′)-monophosphate-adenosine-3′ − 5′)- monophosphate)STING ligand), (7) 7-CH-cAMP/cTuMP (7-Deazaadenosine-3′,5′-cyclic monophosphate; HCN ligand), (8) 2′,3′-cAMP (Adenosine-2′,3′-cyclic monophosphate), (9) 7-PS(O)₂E-8-T-cGMP (7-[2-(Phenylsulfonyl)ethyl]-8-thioguanosine-3′,5′-cyclic monophosphate; selective CNG_olf/ret ligand), (10) 8-[Fluo]-cGMP/8-[Fluo]-AET-cGMP (8-(2-[Fluoresceinyl]aminoethylthio)guanosine-3′,5′-cyclic monophosphate PKG ligand, general cGMP-like binding fluorescence tool), (11) c-hexa-AMP; cyclic hexaadenylate (Cyclic hexa-adenosine monophosphate; CRISPR-CAS III ligand).