Glutamine transporters as pharmacological targets: From function to drug design

Among the different targets of administered drugs, there are membrane transporters that play also a role in drug delivery and disposition. Moreover, drug-transporter interactions are responsible for off-target effects of drugs underlying their toxicity. The improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption, delivery and side effect production. A peculiar group of proteins with great relevance to pharmacology is constituted by the membrane transporters responsible for managing glutamine traffic in different body districts. The interest around glutamine metabolism lies in its physio-pathological role; glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous synthesis. Then, glutamine transporters provide cells with this special nutrient. Among the glutamine transporters, SLC1A5, SLC6A14, SLC6A19, SLC7A5, SLC7A8 and some members of SLC38 family are the best characterized, so far, in both physiological and pathological conditions. Few 3D structures have been solved by CryoEM; other structural data on these transporters have been obtained by computational analysis. Interactions with drugs have been described for several transporters of this group. For some of them, the studies are at an advanced stage, for others, the studies are still in nuce and novel biochemical findings open intriguing perspectives.