With hundreds of solute carrier transporters controlling the movement of critical molecules across cell membranes, researchers argue the SLC family offers a vast and underexploited landscape for neuroscience drug discovery.
Specialised proteins that control the movement of molecules across cell membranes could give researchers a largely untapped source for developing new treatments for neurological and psychiatric diseases, according to a new review of solute carrier (SLC) transporters.
SLCs perform as gatekeepers and workhorses at cell membranes, controlling the movement of sugars, amino acids, ions, vitamins and chemical messengers into and out of cells. Humans have 464 known SLC transporters belonging to 70 families, creating a vast network of molecular traffic that is essential for cellular function.
Researchers say the scale of the SLC family makes it an attractive area for drug discovery, particularly in neuroscience where neurons depend on tightly controlled transport systems to regulate metabolism and communication.
Established drug targets
A small number of SLCs are already proven therapeutic targets. Several widely used neurological and psychiatric medicines work by modifying transporter activity.
Selective serotonin reuptake inhibitors (SSRIs), for example, block the serotonin transporter, preventing serotonin from being taken back up into cells and increasing its availability between neurons. The approach is widely used to treat depression, anxiety disorders and other psychiatric conditions.
SLC transporters are also targeted in epilepsy. Tiagabine inhibits a transporter responsible for GABA uptake, increasing availability of the brain’s principal inhibitory neurotransmitter and helping to reduce excessive neuronal activity.
However, these medicines target only a small proportion of the wider SLC family. Researchers believe many other transporters could provide opportunities for developing treatments for neurological disorders.
From blocking to activating transporters
Most existing SLC-targeting drugs inhibit transporter activity. Researchers are now investigating the potential of doing the opposite by activating, stabilising or restoring transporter function where activity is insufficient or abnormal.
The first candidates using these approaches are already in clinical development, including potential treatments for epilepsy, autism spectrum disorders and chronic pain. These programmes target transporters involved in regulating the balance between excitatory and inhibitory signalling in the brain.
SLCs could also play a role in diseases involving disrupted cellular metabolism. The transporters regulate the movement of nutrients, glucose, ions and metabolic products into and out of cells. Altered energy metabolism is increasingly associated with neurodegenerative diseases including Alzheimer’s and Parkinson’s.
Gene therapy approaches
For disorders directly caused by loss-of-function mutations in SLC genes, researchers are also investigating gene therapies designed to restore transporter activity by providing a functional copy of the affected gene.
Clinical trials are already evaluating approaches for SLC6A1-related neurodevelopmental disorders, GLUT1 deficiency syndrome and a rare disorder caused by mutations in SLC13A5.
The research builds on efforts to systematically study the human ’transportome’, the complete set of transport proteins found in the human body.
Overcoming drug discovery challenges
Despite their potential, SLCs remain technically challenging drug targets. Many transporters are still poorly understood and developing suitable assays and compounds can be difficult.
Advances in structural biology, cryo-electron microscopy, computer-aided drug design and screening technologies are nevertheless improving researchers’ ability to investigate and selectively target previously inaccessible transporters.
Whether these approaches will ultimately produce new treatments for epilepsy, autism, Alzheimer’s or Parkinson’s remains to be established in clinical trials. However, the emergence of candidates in development suggests SLC transporters are becoming an increasingly important frontier in neuroscience drug discovery.
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