High-temperature requirement A serine peptidase (HtrA)

Serine protease HtrA (High-temperature requirement A) is a family of evolutionarily conserved enzymes that function as both molecular chaperones and proteases to maintain protein quality control [1, 5]. In humans, the family consists of four members (HtrA1, HtrA2/Omi, HtrA3, and HtrA4), which are involved in critical cellular processes including apoptosis, cell growth, and extracellular matrix remodeling [2, 6]. HtrA1 is a major therapeutic target in ophthalmology, where its overexpression is linked to the progression of geographic atrophy in age-related macular degeneration (AMD) [7, 14]. HtrA2, localized primarily in the mitochondria, plays a dual role in neuroprotection and the induction of apoptosis, making it a target of interest for Parkinson's disease and oncology [4, 17]. Therapeutic strategies include the use of monoclonal antibodies and small molecule inhibitors to modulate HtrA activity, though challenges such as intraocular inflammation and target selectivity remain [10, 19]. Clinical development has primarily focused on HtrA1 inhibitors for retinal diseases, with several candidates having reached Phase 1 and 2 trials [7, 10].

Other names

High-temperature requirement AHtrA serine peptidaseOmiPRSS11PRSS25DegPL56PARK13

HtrA1 inhibitors (e.g., Galegenimab) target the protease's ability to degrade extracellular matrix components and signaling proteins like DKK3 in the retina [7, 14]. HtrA2 inhibitors (e.g., UCF-101) aim to prevent mitochondrial-mediated apoptosis or preserve mitochondrial integrity in neurodegenerative contexts [4, 18].