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Sierra, Andrés FelipeAuthorAragay GAuthorBallester PCorresponding Author

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Abstract

© 2020 Elsevier Inc. The transport of anions and cations through liposomal membranes facilitated by synthetic carriers has been widely described. In contrast, analogous studies describing the facilitated transport of amino acids (aa) are scarce. We describe the use of calix[4]pyrrole receptors as synthetic carriers for the facilitated diffusion of aa across membranes of liposomes and living cells. We demonstrate that a calix[4]pyrrole cavitand is highly effective and selective for the facilitated diffusion of L-proline (L-Pro). We propose a mobile carrier diffusion mechanism to explain the observed aa facilitated diffusion process. The transport process involves the formation of a 1:1 complex between the carrier and the aa (e.g., L-Pro⊂1). We also describe the unprecedented application of a synthetic carrier to contribute to the uptake of L-Pro in human cells in addition to that mediated by the natural transporters. The reported results augur well for the potential use of aa synthetic carriers in therapeutic applications. Important diseases in the modern society, including cancer, aminoacidurias, and neurodegenerative disorders, might be provoked by missing or defective amino acid transporters at the cell membrane. Synthetic receptors capable of transporting amino acids across cell membranes could serve as therapeutic tools to tackle these diseases. To date, few studies concerning synthetic transporters of amino acids were performed using liposomal membranes. Moreover, as far as we are aware, there are no literature precedents reporting the amino acid transport properties of synthetic receptors through membranes of living cells. This work describes the use of a calix[4]pyrrole-based synthetic carrier for the facilitated transport of amino acids across the membranes of liposomes. It also represents the first account reporting the ability of a synthetic carrier to contribute to the L-Pro influx of living cells. Few studies assess the amino acid transport properties of synthetic carriers using liposomal and cell membranes. Herein, we apply an optimized radiometric assay to demonstrate the selective transport of L-Pro across liposomal membranes by the means of a synthetic calix[4]pyrrole cavitand. Moreover, we show that the carrier also contributes to the overall uptake of L-Pro in HeLa cells. These unprecedented results augur well for the potential application of calix[4]pyrroles as therapeutic tools for L-Pro-dependent diseases, including some cancers and hyperprolinemia.

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