Transmembrane Transport of cAMP and AMP Using a Two Component Small Molecule Transport System

Abstract Nucleotides such as cAMP (cyclic adenosine monophosphate) and AMP (adenosine monophosphate) are central to many cellular processes, but their highly hydrophilic and charged nature prevents passive permeation across lipid bilayers. Here, we report the first example of facilitated transport of cAMP and AMP across liposome membranes using a neutral two‐component system at physiological pH. This system pairs a synthetic anionophore targeting the phosphate group with a thymine derivative to boost transport efficiency. Liposome‐based fluorescence and 31 P NMR experiments confirmed transmembrane transport, supported by control experiments. A fluorinated squaramide proved to be the best transporter and was able to transport cAMP even without the help of a thymine derivative, as well as AMP in the presence of a lipophilic thymine derivative. These findings show that carefully designed small molecules can enable direct nucleotide translocation, with potential applications in drug delivery and synthetic biology.