Nucleopeptide Assemblies Selectively Sequester ATP in Cancer Cells to Increase the Efficacy of Doxorubicin

Abstract

<p class="first" id="P1">Selectively interacting with ATP by synthetic molecules under physiological condition promises many useful applications but remains a challenge. Here we report that assemblies of nucleopeptides selectively sequestrate ATP in complex conditions (e.g., serum and cytosol). We develop assemblies of nucleopeptides that selectively sequester ATP over ADP. Counteracting enzymes interconvert ATP and ADP to modulate the nanostructures formed by the nucleopeptides and the nucleotides. The nucleopeptides, sequestering ATP effectively in cells, slow down efflux pumps in multidrug resistance cancer cells, thus boosting the efficacy of an anticancer drug. Examining additional 11 nucleopeptides (including D- and L-enantiomers) yields five more nucleopeptides that differentiate ATP and ADP via either precipitation or gelation. As the first example of using assemblies of nucleopeptides for interacting with ATP and disrupting intracellular ATP dynamics, this work illustrates the use of supramolecular assemblies to interact with small and essential biological molecules for controlling cell behaviors. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/48992e0a-17a0-4417-98ee-e48d53afef79/PubMedCentral/image/nihms975593u1.jpg"/> </div> </p>