Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.
Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics.
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DOI：
10.1021/jm9012455
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Steinmetzer T
中科院分区：
文献类型：
--
作者：
Becker GL;Sielaff F;Than ME;Lindberg I;Routhier S;Day R;Lu Y;Garten W;Steinmetzer T
Furin属于原蛋白转换酶(PC)家族，参与许多正常的生理和致病过程，如病毒繁殖、细菌毒素激活、癌症和转移。呋喃和相关的呋喃类PC以特征的多碱基共识序列切割它们的底物，优先在精氨酸残基之后。通过在底物类似肽抑制剂的P1位引入脱羧基精氨酸模拟物，我们可以鉴定出高效的呋喃西林抑制剂。最有效的化合物苯乙酰-精氨酸-精氨酸氨基-4-氨基苯甲酰胺(15)对呋喃西林有抑制作用，其Ki值为0.81 nM，对PC1/3、PACE4和PC5/6等其他PC也有类似的亲和力，而PC2和PC7或类胰酶的丝氨酸蛋白酶影响较小。在鸡瘟病毒(甲型H7N1流感)感染的MDCK细胞中，抑制剂15减少了蛋白水解性血凝素的裂解，并在长期感染试验中能够抑制病毒的繁殖。分子模拟揭示了呋喃S1袋中4-氨基苯甲酰胺残基的几个关键相互作用，这有助于这些抑制剂具有良好的亲和力。
Furin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer and metastasis. Furin and related furin-like PCs cleave their substrates at characteristic multibasic consensus sequences, preferentially after an arginine residue. By incorporation of decarboxylated arginine mimetics in P1 position of substrate analogue peptidic inhibitors we could identify highly potent furin inhibitors. The most potent compound, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (15), inhibits furin with a Ki-value of 0.81 nM and has also comparable affinity to other PCs like PC1/3, PACE4, and PC5/6, whereas PC2 and PC7 or trypsin-like serine proteases were poorly affected. In fowl plague virus (influenza A, H7N1)-infected MDCK cells inhibitor 15 reduced proteolytic hemagglutinin cleavage and was able to reduce virus propagation in a long term infection test. Molecular modelling revealed several key interactions of the 4-amidinobenzylamide residue in the S1 pocket of furin contributing to the excellent affinity of these inhibitors.
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影响因子：
4.8
作者：
Bennett, BD;Denis, P;Vassar, R
通讯作者：
Vassar, R
DOI：
10.1038/nsb941
发表时间：
2003-07-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Henrich, S;Cameron, A;Than, ME
通讯作者：
Than, ME
影响因子：
4.1
作者：
Basak, A;Lazure, C
通讯作者：
Lazure, C
影响因子：
3.7
作者：
GARTEN, W;STIENEKE, A;KLENK, HD
通讯作者：
KLENK, HD
DOI：
10.1073/pnas.050504297
发表时间：
2000-03-14
影响因子：
11.1
作者：
Jean, F;Thomas, L;Thomas, G
通讯作者：
Thomas, G