Novel inhibitors of human leukocyte elastase and cathepsin G. Sequence variants of squash seed protease inhibitor with altered protease selectivity.
Novel inhibitors of human leukocyte elastase and cathepsin G. Sequence variants of squash seed protease inhibitor with altered protease selectivity.
复制标题
人类白细胞弹性蛋白酶和组织蛋白酶 G 的新型抑制剂。具有改变的蛋白酶选择性的南瓜籽蛋白酶抑制剂的序列变体。
作者：
C. A. McWherter;W. F. Walkenhorst;E. Campbell;G. Glover
以西葫芦种子中发现的29个氨基酸残基--最大弯曲霉胰蛋白酶抑制因子III(CMTI-III)的P1氨基酸序列变异体为原料，采用固相法合成新型人白细胞弹性蛋白酶(HLE)和组织蛋白酶G(CG)的多肽抑制剂。对P1变异体的系统研究表明，P1、Arg、Lys、Leu、Ala、Phe和Met抑制胰酶；P1、Val、Ile、Gly、Leu、Ala、Phe和Met抑制HLE；P1 Leu、Ala、Phe和Met抑制CG和糜蛋白酶。含有P1、Val、Ile或Gly的变异体是HLE的选择性抑制剂，而抑制胰蛋白酶需要具有未支化的{beta}碳的P1氨基酸。Val-5-CMTI-III(P1Val)对HLE的抑制作用符合1：1结合化学计量比，其结合峰(K{subI}){subAPP}为8.7 nM。Gly-5-CMTI-III对HLE的抑制表明，除P1侧链外，反应部位的结构部分也有重要作用。VAL-5-CMTI-III抑制HLE和人多形核白细胞(PMN)对表面标记的纤维连接蛋白的蛋白分解。VAL-5-CMTI-III比阻止I标记的纤维连接蛋白的溶解更有效地阻止了多肽对硝基苯胺底物的周转。在阻止结缔组织基质的PMN降解方面，它与人血清{α}{sub1}-蛋白水解酶抑制剂几乎一样有效。除了为控制炎性细胞蛋白水解性损伤提供更有趣的候选药物外，基于CMTI的抑制剂还是研究分子识别的理想选择，因为它们体积小，制备容易，而且可以用灵敏和定量的方法进行分子间相互作用。
Novel peptide inhibitors of human leukocyte elastase (HLE) and cathepsin G (CG) were prepared by solid-phase peptide synthesis of P1 amino acid sequence variants of Curcurbita maxima trypsin inhibitor III (CMTI-III), a 29-residue peptide found in squash seed. A systematic study of P1 variants indicated that P1, Arg, Lys, Leu, Ala, Phe, and Met inhibit trypsin; P1, Val, Ile, Gly, Leu, Ala, Phe, and Met inhibit HLE; P1 Leu, Ala, Phe, and Met inhibit CG and chymotrypsin. Variants with P1, Val, Ile, or Gly were selective inhibitors of HLE, while inhibition of trypsin required P1 amino acids with an unbranched {beta} carbon. Studies of Val-5-CMTI-III (P1 Val) inhibition of HLE demonstrated a 1:1 binding stoichiometry with a (K{sub i}){sub app} of 8.7 nM. Inhibition of HLE by Gly-5-CMTI-III indicated a significant role for reactive-site structural moieties other than the P1 side chain. Val-5-CMTI-III inhibited both HLE and human polymorphonuclear leukocyte (PMN) proteolysis of surface-bound {sup 125}I-labeled fibronectin. Val-5-CMTI-III was more effective at preventing turnover of a peptide p-nitroanilide substrate than halting dissolution of {sup 125}I-labeled fibronectin. It was about as effective as human serum {alpha}{sub 1}-proteinase inhibitor in preventing PMN degradation of the connective tissue substrate. In addition to providingmore » interesting candidates for controlling inflammatory cell proteolytic injury, the CMTI-based inhibitors are ideal for studying molecular recognition because of their small size, their ease of preparation, and the availability of sensitive and quantitative assays for intermolecular interactions.« less
肺部炎症期间细胞外基质损伤。
影响因子：
9.6
作者：
Campbell,EJ;Senior,RM;Welgus,HG
通讯作者：
Welgus,HG
人皮肤成纤维细胞胶原酶：与底物和抑制剂的相互作用。
DOI：
10.1016/s0174-173x(85)80038-8
发表时间：
1985
期刊：
Collagen and related research
影响因子：
--
作者：
Welgus,HG;Jeffrey,JJ;Eisen,AZ;Roswit,WT;Stricklin,GP
通讯作者：
Stricklin,GP
中性粒细胞介导的内皮下基质溶解：正常和慢性肉芽肿性疾病吞噬细胞使用的氧化和非氧化蛋白水解机制。
DOI：
--
发表时间：
1986
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Weiss,SJ;Curnutte,JT;Regiani,S
通讯作者：
Regiani,S