Kadowaki Tomoko, Takii Ryosuke, Baba Atsuyo, Yamamoto Kenji
Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Nihon Yakurigaku Zasshi. 2003 Jul;122(1):37-44. doi: 10.1254/fpj.122.37.
The arginine-specific cysteine proteinase (Arg-gingipain, Rgp) and lysine-specific cysteine proteinase (Lys-gingipain, Kgp) are produced by Porphyromonas gingivalis, an etiological bacterium of periodontal disease. Rgp and Kgp have been implicated as the major virulent factors because of their degrading activity to a broad range of host proteins and of the essential roles in bacterial cell viability. Recent studies have demonstrated the association of P. gingivalis with systemic diseases such as cardiovascular diseases, preterm birth, and low birth weight. The majority of gingipains exist as the membrane-associated complexes composed of the proteinase domains of both Rgp and Kgp, the C-terminal adhesin domains of RgpA and Kgp, phospholipids, and LPS. The complex induced potent viability loss of human endothelial cells and fibroblasts. As the suppression of Rgp and Kgp seems to be the most important to overcome the P. gingivalis-induced systemic disorders as well as the periodontal disease, we have thus designed and synthesized novel proteinase inhibitors specific to Rgp and Kgp on the basis of cleavage sites. Some of them suppressed the characteristic features of P. gingivalis associated with its pathogenicity such as degradation of host proteins, hemagglutination, enhancement of vascular permeability, disruption of leukocytes function, and induction of host cell death.
精氨酸特异性半胱氨酸蛋白酶（精氨酸牙龈蛋白酶，Rgp）和赖氨酸特异性半胱氨酸蛋白酶（赖氨酸牙龈蛋白酶，Kgp）由牙龈卟啉单胞菌产生，牙龈卟啉单胞菌是牙周病的病原菌。Rgp和Kgp被认为是主要的致病因素，因为它们对多种宿主蛋白具有降解活性，并且在细菌细胞存活中起重要作用。最近的研究表明牙龈卟啉单胞菌与心血管疾病、早产和低出生体重等全身性疾病有关。大多数牙龈蛋白酶以膜相关复合物的形式存在，该复合物由Rgp和Kgp的蛋白酶结构域、RgpA和Kgp的C末端粘附素结构域、磷脂和脂多糖组成。该复合物可导致人内皮细胞和成纤维细胞的有效活力丧失。由于抑制Rgp和Kgp似乎对克服牙龈卟啉单胞菌引起的全身性疾病以及牙周病最为重要，因此我们基于切割位点设计并合成了对Rgp和Kgp具有特异性的新型蛋白酶抑制剂。其中一些抑制剂抑制了牙龈卟啉单胞菌与其致病性相关的特征，如宿主蛋白降解、血凝、血管通透性增强、白细胞功能破坏和宿主细胞死亡诱导。
