Kallikrein-related peptidase (specifically KLK5 and KLK7) (KLK)

Neutral serine proteases in epidermal tissue, primarily represented by the kallikrein-related peptidase (KLK) family (notably KLK5 and KLK7), are essential enzymes for skin homeostasis. These enzymes, historically known as stratum corneum tryptic enzyme (SCTE) and stratum corneum chymotryptic enzyme (SCCE), are responsible for the controlled degradation of corneodesmosomes, the protein complexes that hold keratinocytes together in the stratum corneum, thereby facilitating desquamation. Their activity is highly pH-dependent, with optimal function at neutral pH, and is naturally regulated by endogenous inhibitors like LEKTI (encoded by the SPINK5 gene). Dysregulation of these proteases, often due to a rise in skin pH or a deficiency in inhibitors, is a hallmark of various dermatological conditions, including Netherton syndrome, atopic dermatitis, and rosacea. In these diseases, excessive proteolytic activity leads to premature desquamation, barrier dysfunction, and the activation of pro-inflammatory signaling via protease-activated receptor 2 (PAR-2). Consequently, these proteases are significant therapeutic targets for topical and systemic inhibitors aimed at restoring skin barrier integrity and reducing inflammatory responses. The term "threonine" in the target name is likely a misnomer or refers to the proteasome, which is a distinct threonine protease also present in the epidermis but typically classified separately from the neutral serine proteases involved in desquamation.

Other names

Neutral serine proteaseStratum corneum tryptic enzyme (SCTE)Stratum corneum chymotryptic enzyme (SCCE)Kallikrein-related peptidase 5 (KLK5)Kallikrein-related peptidase 7 (KLK7)Epidermal neutral serine proteases

Inhibition of proteolytic activity to prevent excessive degradation of corneodesmosomes and reduce pro-inflammatory signaling through PAR-2 activation.