LEKTI-Grafted Sunflower Trypsin Inhibitor: A Potential Therapeutic for Skin Diseases

Kallikrein 5 (KLK5) is a serine protease expressed in the outer skin layers, where it regulates the barrier function by cleaving desmosomal proteins. Elevated KLK5 causes excessive proteolysis, leading to corneocyte overdesquamation and barrier compromise. Increased KLK5 activity has been linked to atopic dermatitis (AD), a chronic inflammatory disease affecting up to 20% of children, highlighting the need for therapies that restore barrier integrity. While many serine protease inhibitors have been developed, most lack KLK5 selectivity. To address this, novel analogues of the sunflower trypsin inhibitor were designed and evaluated. Lead <b>7</b> emerged as a potent (IC₅₀ = 14 ± 4 nM; <i>K_i</i> = 11 nM) selective KLK5 inhibitor. In keratinocytes from a Netherton syndrome patient, lead <b>7</b> significantly reduced the KLK5 activity and improved epithelial barrier integrity, as shown by transepithelial electrical resistance. These findings suggest lead <b>7</b> as a potential therapy for AD and other conditions with elevated KLK5 activity.