Structure, function, and pharmacology of human nucleoside transporters

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2022

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Abstract

Nucleosides are small polar biomolecules that play important roles in every aspect of cellular life. Due to their impermeability to lipid bilayers, dedicated integral membrane proteins are tasked with selective transport of nucleosides across biological membranes. In humans, two genetically distinct protein families mediate nucleoside membrane transport: the concentrative and equilibrative nucleoside transporter families. Owing to the roles played by nucleoside transporters in physiology, pathophysiology, and pharmacology of nucleoside-analog therapeutics, a mechanistic understanding of human nucleoside transporters would not only advance our understanding of transporter biology in general but would also uncover exploitable pharmacological features for future drug development efforts. In this work, we first determined X-ray crystal structures of the human equilibrative nucleoside transporter in complex with two different adenosine reuptake inhibitors. Using our structural data as a starting point, we then designed and synthesized a series of novel transporter inhibitors with improved pharmacological properties. We also interrogated the role of both concentrative and equilibrative nucleoside transporters in nucleoside-analog antiviral drug pharmacological properties using biochemical experiments, viral assays, and cryo-electron microscopy.

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Wright, Nicholas James (2022). Structure, function, and pharmacology of human nucleoside transporters. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25771.

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