John R J, Rusznak C, Ramjee M, Lamont A G, Abrahamson M, Hewitt E L
Peptide Therapeutics Ltd, Biology Department, Peterhouse Technology Park, Cambridge, UK.
Clin Exp Allergy. 2000 Jun;30(6):784-93. doi: 10.1046/j.1365-2222.2000.00840.x.
The house dust mite (HDM) Dermatophagoides pteronyssinus is an important source of allergens, which can cause allergic conditions. The cysteine protease activity of Der p 1 may enhance the potency of this major mite allergen through cleavage of CD23 and CD25 from the surface of immune cells, IgE independent mast cell activation, increases in epithelial cell permeability and inactivation of an endogenous serine protease inhibitor. Inhibition of the enzymatic activity of Der p 1 may therefore be of therapeutic benefit.
To examine the activity of PTL11028, a newly developed Der p 1 inhibitor, in a range of assays that directly or indirectly measure Der p 1 protease activity and to compare its activity to endogenous cysteine protease inhibitors.
The proteolytic activities of purified Der p 1 or HDM extract and inhibitory properties of PTL11028 were examined through cleavage of an artificial peptidyl substrate, cleavage of CD23 from human B cells and permeability studies on primary human bronchial epithelial cells.
PTL11028 is a highly potent and specific Der p 1 inhibitor, being effective against both purified protease and Der p 1 within HDM extract. PTL11028 can completely inhibit Der p 1-mediated CD23 cleavage from human B cells and also reduces HDM-induced human bronchial epithelial cell permeability by 50%. Der p 1 is potently inhibited by cystatin A and to a lesser extent by cystatins C and E/M.
PTL11028 is a highly potent and selective irreversible inhibitor of the cysteine protease activity of Der p 1, an activity that may be modulated in vivo by some human cystatins. PTL11028 prevents the Der p 1-mediated cleavage of CD23 from human B cells and significantly reduces HDM-induced permeabilization of the epithelial barrier. PTL11028 is an important tool to examine the biological effects of Der p 1 in a range of in vitro and in vivo model systems.
屋尘螨（HDM）柏氏禽刺螨是过敏原的重要来源，可引发过敏反应。Der p 1的半胱氨酸蛋白酶活性可能通过从免疫细胞表面切割CD23和CD25、非IgE依赖的肥大细胞激活、增加上皮细胞通透性以及使内源性丝氨酸蛋白酶抑制剂失活来增强这种主要螨类过敏原的效力。因此，抑制Der p 1的酶活性可能具有治疗益处。
在一系列直接或间接测量Der p 1蛋白酶活性的试验中检测新开发的Der p 1抑制剂PTL11028的活性，并将其活性与内源性半胱氨酸蛋白酶抑制剂进行比较。
通过人工肽基底物的切割、人B细胞中CD23的切割以及原代人支气管上皮细胞的通透性研究，检测纯化的Der p 1或HDM提取物的蛋白水解活性以及PTL11028的抑制特性。
PTL11028是一种高效且特异性的Der p 1抑制剂，对纯化的蛋白酶和HDM提取物中的Der p 1均有效。PTL11028可完全抑制Der p 1介导的人B细胞中CD23的切割，还可使HDM诱导的人支气管上皮细胞通透性降低50%。Der p 1受到胱抑素A的强烈抑制，而受到胱抑素C和E/M的抑制程度较小。
PTL11028是Der p 1半胱氨酸蛋白酶活性的高效、选择性不可逆抑制剂，某些人胱抑素可能在体内调节该活性。PTL11028可防止Der p 1介导的人B细胞中CD23的切割，并显著降低HDM诱导的上皮屏障通透性。PTL11028是在一系列体外和体内模型系统中研究Der p 1生物学效应的重要工具。
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