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The 3--5-cyclic adenosine monophosphate (cAMP)/PKA pathway represents a major target for pharmacological intervention in multiple disease conditions. Although the last decade saw the concept of highly compartmentalized cAMP/PKA signaling consolidating, current means for the manipulation of this pathway still do not allow to specifically intervene on discrete cAMP/PKA microdomains. Since compartmentalization is crucial for action specificity, identifying new tools that allow local modulation of cAMP/PKA responses is an urgent need. Among key players of cAMP/PKA signaling compartmentalization, a major role is played by A-kinase anchoring proteins (AKAPs) that, by definition, anchor PKA, its substrates and its regulators within multiprotein complexes in well-confined subcellular compartments. Different tools have been conceived to interfere with AKAP-based protein--protein interactions (PPIs), and these primarily include peptides and peptidomimetics that disrupt AKAP-directed multiprotein complexes. While these molecules have been extensively used to understand the molecular mechanisms behind AKAP function in pathophysiological processes, less attention has been devoted to their potential application for therapy. In this review, we will discuss how AKAP-based PPIs can be pharmacologically targeted by synthetic peptides and peptidomimetics. Introduction The 3--5-cyclic adenosine monophosphate (cAMP) second messenger controls different biological processes and signaling pathways primarily via the activation of protein kinase A (PKA), one of the most widely researched serine/threonine kinases [1,2]. Several stimuli, such as catecholamines and neurotransmitters, bind to G protein-coupled receptors (GPCRs), and trigger the activation of heterotrimeric G proteins which, in turn, stimulate adenylate cyclase (AC) to produce cAMP fromATP. This second messenger binds the dimer of PKA regulatory subunits, promoting the release and activation of the two catalytic components of the PKA holoenzyme, which are then free to phosphorylate a multitude of intracellular substrates. Alternatively, cAMP can activate other effectors, including cyclic nucleotide-gated ion channels (CNGs) [3], Popeye domain containing proteins (POPDC) [4], and the exchange protein directly activated by cAMP (EPAC) [5]. This limited number of cAMP-dependent signal transducers appears insufficient to explain the variety of distinct cellular responses elicited by the same second messengermolecule cAMP. Therefore, the specificity of response triggered by this highly diffusible second messenger must be tightly regulated, both spatially and temporally, through further layers of complexity. The current view implies that cyclic nucleotide signals are in fact compartmentalized within the cell by localized multiprotein complexes, also known as cAMP signalosomes, that allow confined generation and destruction of cAMP as well as selective involvement of distinct signal transducers. These complexes restrain signal diffusion, assuring concentration of cAMP in subcellular domains and avoiding leakage of this secondarymessenger molecule to unwanted effectors [6]. These space-restricted signalosomes generally span in their size from the nano to the micrometer scale and frequently include a selective GPCR and its preferentially activated AC isoform ©2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 3259 Downloaded from http://portlandpress.com/clinsci/article-pdf/134/24/3259/900532/cs-2020-1244.pdf by EBSCO Information Services (EIS Ipswich), spochammala@ebsco.com on 10 March 2021 [ABSTRACT FROM AUTHOR]