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

Area of Science:

• Biochemistry
• Dermatology
• Pharmacology

Background:

• Kallikrein 5 (KLK5) is a skin protease regulating barrier function by cleaving desmosomal proteins.
• Elevated KLK5 activity causes excessive proteolysis, leading to skin barrier compromise and is linked to atopic dermatitis (AD).
• Existing serine protease inhibitors often lack KLK5 selectivity, necessitating targeted therapeutic development.

Purpose of the Study:

• To design and evaluate novel selective inhibitors targeting Kallikrein 5 (KLK5).
• To identify a potent therapeutic agent for conditions characterized by elevated KLK5 activity and compromised skin barrier function.

Main Methods:

• Design and synthesis of novel analogues based on the sunflower trypsin inhibitor scaffold.
• Biochemical assays to determine inhibitor potency (IC50, Ki) and selectivity against KLK5.
• In vitro studies using patient-derived keratinocytes to assess KLK5 activity and epithelial barrier integrity (transepithelial electrical resistance).

Main Results:

• Lead compound 7 demonstrated potent (IC50 = 14 ± 4 nM; Ki = 11 nM) and selective inhibition of KLK5.
• In Netherton syndrome patient keratinocytes, lead 7 significantly reduced KLK5 activity.
• Treatment with lead 7 improved epithelial barrier integrity, as evidenced by increased transepithelial electrical resistance.

Conclusions:

• Lead 7 represents a promising therapeutic candidate for managing conditions associated with elevated KLK5 activity.
• The development of selective KLK5 inhibitors like lead 7 offers a potential strategy to restore skin barrier integrity in diseases such as atopic dermatitis.