Serine protease inhibitor Kazal-type 5 (LEKTI) (SPINK5)

Serine protease inhibitor Kazal-type 5 (LEKTI), encoded by the SPINK5 gene, is a multi-domain protein secreted in the epidermis that plays a critical role in maintaining skin barrier integrity (UniProt Q9NQ38). It functions by inhibiting several serine proteases, most notably Kallikrein-related peptidases (KLK5, KLK7, and KLK14) and Elastase 2 (ELA2), which are responsible for the controlled degradation of corneodesmosomes during desquamation (PubMed: 15155614). In conditions like Netherton syndrome, a loss-of-function mutation in SPINK5 leads to a deficiency of LEKTI, resulting in the uncontrolled activity of these proteases (PubMed: 10932194). This hyperactivity causes premature breakdown of the skin barrier, leading to severe ichthyosis, skin inflammation, and increased permeability to allergens (PubMed: 12533514). Therapeutic approaches focus on either replacing the missing LEKTI protein or using small molecule inhibitors to target the downstream overactive proteases, particularly KLK5 and KLK7, to restore homeostatic balance and improve skin health (Quoin Pharmaceuticals, 2024).

Other names

Lympho-epithelial Kazal-type-related inhibitorLEKTIVAKTINETSSPINK5

Restoration of the protease/antiprotease balance in the stratum corneum by inhibiting overactive kallikrein-related peptidases (KLK5, KLK7, KLK14) and elastase 2, thereby preventing premature corneodesmosome degradation.