Abstract
Essential nutrients are attractive targets for the transport of biologically active agents across cell membranes, since many are substrates for active cellular importation pathways. The sodium-dependent multivitamin transporter (SMVT) is among the best characterized of these, and biotin derivatives have been its most popular targets. We have surveyed 45 derivatives of pantothenic acid, another substrate of SMVT, long known as a competitive inhibitor of biotin transport. Variations of the β-alanyl fragment of pantothenate were uniformly rejected by the transporter, including derivatives with very similar steric and acidic characteristics to the natural substrate. The secondary hydroxyl of the 2,2- dimethyl-1,3-propanediol (pantoyl) fragment was the only position at which potential linkers could be attached while retaining activity as an inhibitor of biotin uptake and a substrate for sodium-dependent transport. However, triazole conjugates to several drug-like cargo motifs were not accepted as substrates by human SMVT in cell culture. Two compounds were observed which did not inhibit biotin uptake but were themselves transported in a sodium-dependent fashion, suggesting more complex behavior than expected. These studies represent the most extensive examination to date of pantothenate as an anchor for SMVT-mediated drug delivery, showing that this route requires further investigation before being judged promising.
Keywords: Pantothenic acid, Sodium-dependent multivitamin transporter (SMVT), Biotin transport, Essential nutrient transport, drug delivery.
Current Topics in Medicinal Chemistry
Title:High Specificity in Response of the Sodium-Dependent Multivitamin Transporter to Derivatives of Pantothenic Acid
Volume: 13 Issue: 7
Author(s): Srinivas Reddy Chirapu, Charles J. Rotter, Emily L. Miller, Manthena V. Varma, Robert L. Dow and M.G. Finn
Affiliation:
Keywords: Pantothenic acid, Sodium-dependent multivitamin transporter (SMVT), Biotin transport, Essential nutrient transport, drug delivery.
Abstract: Essential nutrients are attractive targets for the transport of biologically active agents across cell membranes, since many are substrates for active cellular importation pathways. The sodium-dependent multivitamin transporter (SMVT) is among the best characterized of these, and biotin derivatives have been its most popular targets. We have surveyed 45 derivatives of pantothenic acid, another substrate of SMVT, long known as a competitive inhibitor of biotin transport. Variations of the β-alanyl fragment of pantothenate were uniformly rejected by the transporter, including derivatives with very similar steric and acidic characteristics to the natural substrate. The secondary hydroxyl of the 2,2- dimethyl-1,3-propanediol (pantoyl) fragment was the only position at which potential linkers could be attached while retaining activity as an inhibitor of biotin uptake and a substrate for sodium-dependent transport. However, triazole conjugates to several drug-like cargo motifs were not accepted as substrates by human SMVT in cell culture. Two compounds were observed which did not inhibit biotin uptake but were themselves transported in a sodium-dependent fashion, suggesting more complex behavior than expected. These studies represent the most extensive examination to date of pantothenate as an anchor for SMVT-mediated drug delivery, showing that this route requires further investigation before being judged promising.
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Cite this article as:
Chirapu Srinivas Reddy, Rotter Charles J., Miller Emily L., Varma Manthena V., Dow Robert L. and Finn M.G., High Specificity in Response of the Sodium-Dependent Multivitamin Transporter to Derivatives of Pantothenic Acid, Current Topics in Medicinal Chemistry 2013; 13 (7) . https://dx.doi.org/10.2174/1568026611313070006
DOI https://dx.doi.org/10.2174/1568026611313070006 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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