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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Pharmacological Modulation of p53 Function in Cancer Therapy
Current Signal Transduction Therapy Association of Low Vitamin D with Complications of HIV and AIDS: A literature Review
Infectious Disorders - Drug Targets Targeting the Ubiquitin-Proteasome Pathway: An Emerging Concept in Cancer Therapy
Current Topics in Medicinal Chemistry Artepillin C Induces Selective Oxidative Stress and Inhibits Migration and Invasion in a Comprehensive Panel of Human Cervical Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Overview of Current Practice and Future Trends in Thromboprophylaxis for General Surgery
Vascular Disease Prevention (Discontinued) Cancer: A Problem of Developmental Biology; Scientific Evidence for Reprogramming and Differentiation Therapy
Current Drug Targets Acridone-based Antitumor Agents: A Mini-review
Anti-Cancer Agents in Medicinal Chemistry Are Catechins, Polyphenols in Tea, Good for Your Health?
Current Nutrition & Food Science Interplay of Drug Metabolizing CYP450 Enzymes and ABC Transporters in the Blood-Brain Barrier
Current Drug Metabolism Meta Analysis of Advanced Cancer Survival Data Using Lognormal Parametric Fitting: A Statistical Method to Identify Effective Treatment Protocols
Current Pharmaceutical Design Targeting Tumors with Small Molecule Peptides
Current Cancer Drug Targets Cellular and Physiological Effects of Probiotics and Prebiotics
Mini-Reviews in Medicinal Chemistry Gene Expression Assay in the Management of Early Breast Cancer
Current Medicinal Chemistry Recent Developments in Patents Targeting Toll-Like Receptor Genes
Recent Patents on DNA & Gene Sequences Relaxin-Like Peptides in Neoplastic Lesions
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Inhibition of Polo-Like Kinase 1 by BI2536 Reverses the Multidrug Resistance of Human Hepatoma Cells In Vitro and In Vivo
Anti-Cancer Agents in Medicinal Chemistry Dysregulation of LncRNAs in Placenta and Pathogenesis of Preeclampsia
Current Drug Targets Modulation of T Cell Proliferation Through the LIGHT-HVEM-BTLA Cosignaling Pathway
Recent Patents on DNA & Gene Sequences Involvement of Leukotriene Pathway in the Pathogenesis of Ischemia- Reperfusion Injury and Septic and Non-Septic Shock
Current Vascular Pharmacology Imaging in Inflammatory Bowel Disease Mucosal Healing in Ulcerative Colitis: Relevance for Clinical Outcomes
Current Drug Targets