Uncovering the rules governing metabolite and drug transport in the kidney.

To survive and thrive, our bodies must constantly exchange nutrients and their metabolic breakdown products with the environment. The main sites of nutrient uptake, retention and elimination in our bodies are the lungs, intestines, liver and kidneys. These organs have evolved to recognise and transport specific nutrients from the environment into our bloodstream, where they can be transported to energy-requiring organs, such as the muscles and central nervous system. Conversely, these organs also eliminate harmful waste products and environmental toxins from the body, maintaining homeostasis. Central to this function are solute carrier transporters or SLCs. SLCs function as gated pores in the cellular membranes separating our bodies from the environment and can actively pump in or pump out nutrients, toxins and drugs. However, we currently do not understand the molecular details, or rules, underpinning which nutrients are efficiently absorbed, or eliminated. This knowledge gap reduces the effectiveness of prescription drugs, which are often eliminated too quickly, or during combination therapy, can build up in our bodies and result in toxicity, as occurs with many antiviral and anticancer medications. This project focuses on our kidneys, which are particularly susceptible to drug induced toxicity. Within the kidneys, specific sets of SLCs control nutrient exchange and drug recognition. Principal among these are the organic anion transporters (OATs), which are responsible for recognising many clinically prescribed drugs, including anti-inflammatory medications such as ibuprofen and antibiotics, such as penicillin, as well as antivirals and anticancer agents. However, the concentration of these molecules in our cells can result in acute cellular toxicity, and in cases of long-term medication and exposure, can lead to kidney failure and the need for kidney transplants. Limiting the toxicity of medications is a key aim of modern molecular medicine, which focuses on modulating the activity and function of OATs in particular. Remarkably, the molecular basis by which OATs distinguish between metabolites, drugs and inhibitors remains unknown, restricting efforts to understand fundamental kidney biochemistry and, from a clinical perspective, design subfamily-specific inhibitors or modulators to precisely control drug pharmacokinetics. Recently our team used electron microscopy to image, at atomic detail, OAT1, the founding member and a critical kidney transporter. We revealed that OAT1 is regulated by the presence of chloride, which changes as our bodies become more or less hydrated, and how OAT1 interacts with an antiviral drug and clinical inhibitor. However, OAT1 is only one of five major OAT transporters that regulate anion and drug transport in the kidney. Our goal in this project is to apply the latest structural biology techniques, combined with biophysics and biochemistry, to understand the rules governing organic anion transport in our cells. Specifically, we will explain how OAT transporters recognise diverse ligands, such as uric acid, steroid hormones, chemotherapeutic drugs and anti-inflammatories. We will establish the principles and rules governing renal organic anion transport and regulation and explore whether synthetic antibodies can be used to inhibit OAT function in the cell. Specific inhibitors of OATs would have substantial benefit in both fundamental research and offer exciting opportunities to improve clinical treatment. This work will significantly impact a wide range of research disciplines, particularly membrane transport, metabolism, antibody design, cell physiology, and drug development. In addition, we will gain fundamental insights into an essential aspect of renal function and drug/toxin clearance in the body.