Pre-haptoglobin 2 (Zonulin) (HP2)

Pre-haptoglobin 2, commonly known as zonulin, is the only known physiological modulator of intercellular tight junctions that regulates intestinal permeability [2, 5, 11]. It is primarily released from the liver and enterocytes in response to environmental triggers such as gluten-derived gliadin or enteric bacteria [4, 5, 12, 18]. Once released, zonulin binds to a receptor complex consisting of the epidermal growth factor receptor (EGFR) and protease-activated receptor 2 (PAR2), initiating a signaling cascade that leads to the phosphorylation and disassembly of tight junction proteins like zonula occludens-1 (ZO-1) and occludin [3, 4, 11]. This process increases paracellular permeability, allowing the translocation of antigens from the intestinal lumen into the systemic circulation, which can trigger inflammatory and autoimmune responses [4, 5, 8, 15]. Pathological overexpression of zonulin is a key factor in the development of 'leaky gut' and has been implicated in the pathogenesis of Celiac disease, type 1 diabetes, and inflammatory bowel disease [4, 5, 8, 15, 22]. Therapeutic intervention focuses on antagonizing this pathway to restore intestinal barrier integrity [1, 3, 15]. Larazotide acetate (AT-1001) is a synthetic peptide that acts as a zonulin antagonist, preventing the opening of tight junctions and reducing the symptoms associated with gluten exposure in Celiac patients [1, 3, 7, 10]. While zonulin is a promising biomarker for intestinal health, recent challenges regarding the specificity of commercial detection assays have highlighted the need for more precise diagnostic tools in clinical practice [14, 17].

Other names

ZonulinHaptoglobin 2 precursorpre-HP2AT-1001 target

Larazotide acetate acts as a zonulin antagonist that prevents the disassembly of tight junctions by blocking the zonulin receptor complex (EGFR/PAR2) or inhibiting zonulin binding, thereby restoring intestinal barrier function [1, 3, 9, 10].