ABSTRACT
An important step in cyclic nucleotide research was the synthesis and development of cyclic nucleotide analogues (CNAs).15 The design of radiolabeled cyclic nucleotides allowed the measurement of cellular cyclic nucleotide levels and gave rise to the rst in vitro binding assays.16-18
Furthermore, advanced CNA synthesis coupled with chemical proteomics has led not only to the identication of new cyclic nucleotide binding proteins but also to a better understanding of cyclic nucleotide signaling interactomes.19-21
The development of nonhydrolyzable CNAs further extends the application in in-cell assays where degradation by PDEs is problematic for monitoring biological processes in response to fast uctuating cyclic nucleotide levels.15 Another landmark was the synthesis of both agonists (activating) and antagonists (inhibiting) of cyclic nucleotide-dependent protein kinases (PKA and PKG) leading to a better understanding of the physiological roles of the respective effector proteins.22-24 Membranepermeable CNAs now allow the study of cyclic nucleotide signaling in vivo.25 With some effectors being important drug targets, such analogues have the potential to be applied in a pharmacological context.15
