Structural and functional characterization of solute carriers - key players in cellular transport and drug delivery

Project Overview

Number of disease associations (y axis) and small compound interactions (IC50 smaller than 10μM; x ...

Cartoon illustrating the cellular location and solute transport through members of the SLC ...

Typical workflow of purification, crystallization and structure determination for a human SLC. ...

Project Overview

The solute carrier (SLC) family is the largest class of transport-related membrane proteins involved in the transport of a broad range of different substrates across biological membranes, encompassing more than 400 human members. Several approved drugs target SLCs, and a quarter of all SLC genes have been associated with human diseases. The SLC family has gained attention by the pharmaceutical industry, because many members are important drug targets and their specific transport activity can be exploited to deliver drugs resembling the native substrates, for the treatment of cancer, inflammatory diseases and viral infections. Moreover, conjugation of pharmaceuticals to native substrates can facilitate targeted drug delivery (“nanocarrier”), resulting in improved bioavailability. This conjugation approach allows otherwise impermeable compounds to cross the blood brain barrier, thus enhancing the efficacy of neuro-therapeutics for CNS diseases. 

The PhD student will be working closely with other members of my research group at the Structural Genomics Consortium Oxford and collaborate with academic and pharma partners within the ReSOLUTE (Research empowerment on solute carriers) consortium (https://re-solute.eu/), a public-private research partnership supported by the Innovative Medicines Initiative (IMI). A major focus will be the recombinant production of human SLC family members for structural studies by X-ray crystallography or cryo-EM, as well as for the generation of antibodies and other affinity reagents, such as monobodies, sybodies or DARPins. These affinity reagents are powerful tools that can be used as crystallization chaperones, to modulate transport in functional assays and to facilitate single-particle cryo-electron microscopy. The primary goal of this research is to determine the overall architecture of human SLC transporters and to investigate their function in cellular and cell-free assays. The results from these studies will shed light onto the molecular mechanisms of transport by solute carriers and improve our knowledge regarding their substrate specificity and their interactions with drugs and xenobiotics.

Training Opportunities

Training Opportunities

Theme

Protein Science & Structural Biology and Genetics & Genomics

Admissions

Project reference number: 833

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Katharina Duerr Structural Genomics Consortium Oxford University, Old Road Campus Research Building GBR katharina.duerr@sgc.ox.ac.uk
Professor Frank von Delft Structural Genomics Consortium Oxford University, Old Road Campus Research Building GBR frank.vondelft@sgc.ox.ac.uk

Lin L, Yee SW, Kim RB, Giacomini KM. 2015. SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov, 14 (8), pp. 543-60. Read abstract | Read more

Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets. Hide abstract

César-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G, Bai X, Reithmeier RA, Hepworth D, Hediger MA, Edwards AM, Superti-Furga G. 2015. A Call for Systematic Research on Solute Carriers. Cell, 162 (3), pp. 478-87. Read abstract | Read more

Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space. Hide abstract

Rask-Andersen M, Masuram S, Fredriksson R, Schiöth HB. 2013. Solute carriers as drug targets: current use, clinical trials and prospective. Mol. Aspects Med., 34 (2-3), pp. 702-10. Read abstract | Read more

Solute carriers (SLCs) comprise a large family of membrane transporters responsible for the transmembrane transport of a wide variety of substrates such as inorganic ions, amino acids, neurotransmitters and sugars. Despite being the largest family of membrane transport proteins, SLCs have been relatively under-utilized as therapeutic drug targets by approved drugs. In this paper, we aim to catalogue therapeutic SLCs utilized by approved drugs or currently in clinical trials. By mining information on clinical trials from the Centerwatch.com "drugs in clinical trials database" we were able to identify potentially novel SLC drug targets currently under development. We also searched the literature for SLCs that have been discussed as future therapeutic drug targets. We find SLCs to be utilized as therapeutic targets in treatment of a wide variety of diseases and disorders, such as major depression, ADHD, osteoporosis and hypertension. Drugs targeting SLCs for treatment of diabetes, constipation and hypercholesterolaemia are currently in clinical trials. SLC drug targets have also been explored in clinical trials for cardioprotection after an ischemic event. SLCs are of particular interest as targets in antineoplastic treatment and for the targeted transport of cytotoxic drugs into tumors, e.g. via the glucose transporters GLUT1-5 and SGLT1-3. Hide abstract

Murakami T. 2016. A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability. J Pharm Sci, 105 (9), pp. 2515-26. Read abstract | Read more

Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration. Hide abstract