Folate-binding and transport proteins

Folate-binding and transport proteins are a group of membrane-associated proteins and transporters essential for the cellular uptake and systemic distribution of folates (vitamin B9), which are critical for DNA synthesis and one-carbon metabolism (UniProt: P15328, PubMed: 10078775). This group primarily includes the high-affinity Folate Receptors (FR-alpha/FOLR1, FR-beta/FOLR2, and FR-gamma/FOLR3), the Reduced Folate Carrier (RFC/SLC19A1), and the Proton-Coupled Folate Transporter (PCFT/SLC46A1) (NIH: PMC3526981). Folate Receptor alpha is frequently overexpressed in various epithelial cancers, such as ovarian and lung cancer, making it a prominent target for antibody-drug conjugates (ADCs) like mirvetuximab soravtansine and folate-targeted imaging agents (PubMed: 36375117). The transporters RFC and PCFT are the primary routes for the entry of classical antifolates like methotrexate and pemetrexed into cells, and their expression levels often dictate drug sensitivity or resistance (PubMed: 23139236). Dysregulation of these proteins is linked to folate deficiency syndromes, neural tube defects, and oncogenesis, while their selective expression patterns are exploited for targeted cancer therapies and diagnostic imaging (Wikipedia: Folate targeting). These proteins also play a role in inflammatory diseases, where FR-beta is expressed on activated macrophages, providing a target for anti-inflammatory drug delivery (PubMed: 15155835).

Other names

Folate receptorsFolate transportersFolate carriersFolate-binding proteinFBPFolate receptor alphaReduced folate carrierProton-coupled folate transporterFOLR1SLC19A1SLC46A1

Drugs targeting these proteins primarily act through: 1) Targeted delivery of cytotoxic payloads via receptor-mediated endocytosis (e.g., ADCs and folate-drug conjugates targeting FOLR1); 2) Competitive inhibition of folate transport into cells (e.g., antifolates like methotrexate and pemetrexed); and 3) Monoclonal antibody-mediated blockade of receptor function or induction of antibody-dependent cellular cytotoxicity (ADCC).