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August 25, 2003
Volume 81, Number 34
CENEAR 81 34 p. 40
ISSN 0009-2347


Method Targets Transporter Proteins To Deliver Drugs


Protein transduction is not the only way to deliver drugs into cells. XenoPort, a Santa Clara, Calif.-based company, is hijacking proteins known as solute carrier transporters within the cell membrane to convey small-molecule drugs across biological barriers.

XenoPort especially addresses issues of poor bioavailability, says Ronald W. Barrett, president and chief executive officer. "One of the major problems in the area of bioavailability is the absorption of molecules from the GI [gastrointestinal] tract," he says. "The conventional and historical way of thinking about oral drug permeability" is that the molecule is passively absorbed into those cells.

As they looked at the problem of bioavailability, XenoPort scientists saw that many drugs were actually getting into cells by hijacking transporters. "We thought it was an opportune time to turn this into a more proactive approach to understand what the transporters are in the GI tract, to set up assays for those transporters, and to specifically design molecules to use those transporters," Barrett says.

There are more than 200 different solute carrier transporters that recognize different types of molecules. "We have identified those transporters in the GI tract that we think fit the criteria of being abundantly expressed, so they would be able to move significant amounts of drug molecules across the GI tract without fear of getting into a situation where we have competition from food," Barrett says. "The second criterion is that they have a structural specificity that isn't too tight. After all, we have to fool [the transporter] into thinking that our drug is a nutrient. We look for those transporters that are somewhat promiscuous in terms of what they will recognize."

XenoPort researchers target these transporters by attaching chemical modules, which they call "XenoPorter molecules," to the drug being delivered. The combination of drug and XenoPorter molecule can be either a prodrug, in which the XenoPorter molecule is cleaved immediately after delivery, or a permanent conjugate. The choice between permanent conjugate and prodrug depends largely on how far advanced the drug candidate is. If safety and efficacy are already well established for the isolated drug, the combination is designed as a prodrug.

XenoPort divides its molecules into two types. In the first type, the drug candidate has no features that can be recognized by the transporter being targeted, so the added portion has to provide all the recognition elements. In the second case, some drugs may have some but not all of the features required for transport. They only need to be slightly modified to target transporters.

"In some cases, we actually use features of the drug molecule as part of the recognition domain. For example, it might have a monocarboxylate functionality but there's something else on the molecule that's preventing it from being recognized by a monocarboxylate transporter," Barrett says. "It's a bit of crafting and customization based on the structure of the drug molecule and based on our knowledge of what these different transporters like to see in terms of chemical structure to be recognized as a substrate."

XenoPort's most advanced project involves the epilepsy drug gabapentin. The drug is normally absorbed in the small intestine through a type of transporter called a large neutral amino acid transporter. However, this transporter has a limited transport capacity. XenoPort is instead targeting different transporters using a prodrug that improves the absorption efficiency and can be absorbed in both the small and large intestine.

Cover Story
Protein transduction and similar methods are promising techniques for delivering a wide variety of drugs directly into cells

Synthetic Receptors Pull Molecules Into Cells

Method Targets Transporter Proteins To Deliver Drugs


Chemical & Engineering News
Copyright © 2003 American Chemical Society


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