A highly conserved, inhibitable astacin metalloprotease from Teladorsagia circumcincta is required for cuticle formation and nematode development.
A highly conserved, inhibitable astacin metalloprotease from Teladorsagia circumcincta is required for cuticle formation and nematode development.
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DOI：
10.1016/j.ijpara.2015.01.004
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发表时间：
2015-04
影响因子：
4
通讯作者：
Page, Antony P.
中科院分区：
文献类型：
--
作者：
Stepek, Gillian;McCormack, Gillian;Winter, Alan D.;Page, Antony P.
关键词：
Astacin金属蛋白酶DPY-31在整个线虫门中是保守的。DPY-31是环纹Teladorsagia circumcincta角质层形成的关键。基质金属蛋白酶抑制剂对重组DPY-31有效。新型异羟肟酸抑制剂引起线虫的Dumpy和Moult缺陷。DPY-31是未来线虫防治的潜在靶标。寄生线虫在全世界范围内引起牲畜和人类的慢性、使人衰弱的感染，并且许多寄生线虫已经对目前可用的驱虫剂产生了多重耐药性。这些寄生虫的保护性胶原角质层是线虫生存所必需的，其合成在自由生活的线虫秀丽隐杆线虫中已被广泛研究。胶原合成途径是一个复杂的多步骤过程，涉及许多关键酶，包括astacin金属蛋白酶。线虫对C.线虫发育，在孵化、蜕皮和角质层合成中具有特定作用。NAS-35（也称为DPY-31）是脊椎动物前胶原C蛋白酶的同源物，并且在C. elegans，因为它的突变导致温度敏感的致命性和角质层缺陷。绵羊胃肠道线虫Teladorsagia circumcincta DPY-31的特性及其拯救C.描述了elegans突变体。具有异羟肟酸酯官能团的化合物先前已被证明是前胶原C-蛋白酶的有效抑制剂，因此检测了对T.包皮环切酶针对T.的表型筛选circumcincta、捻转血矛线虫（Haemonchus contortus）和C.线虫幼虫阶段鉴定了引起与抑制涉及角质层胶原蛋白合成的蛋白酶一致的身体形态表型的化合物。这些化合物对重组T. circumcincta DPY-31，支持该酶可能代表潜在的新型驱虫药物靶标的假设。
Astacin metalloprotease, DPY-31, is conserved throughout the nematode phylum. DPY-31 is crucial to Teladorsagia circumcincta cuticle formation. Matrix metalloprotease inhibitors are efficacious against recombinant DPY-31. Novel hydroxamate inhibitors caused Dumpy and Moult defects in nematodes. DPY-31 is a potential target for future nematode control. Parasitic nematodes cause chronic, debilitating infections in both livestock and humans worldwide, and many have developed multiple resistance to the currently available anthelmintics. The protective collagenous cuticle of these parasites is required for nematode survival and its synthesis has been studied extensively in the free-living nematode, Caenorhabditis elegans. The collagen synthesis pathway is a complex, multi-step process involving numerous key enzymes, including the astacin metalloproteases. Nematode astacinsare crucial for C. elegans development, having specific roles in hatching, moulting and cuticle synthesis. NAS-35 (also called DPY-31) is a homologue of a vertebrate procollagen C-proteinase and performs a central role in cuticle formation of C. elegans as its mutation causes temperature-sensitive lethality and cuticle defects. The characterisation of DPY-31 from the ovine gastrointestinal nematode Teladorsagia circumcincta and its ability to rescue the C. elegans mutant is described. Compounds with a hydroxamate functional group have previously been shown to be potent inhibitors of procollagen C-proteinases and were therefore examined for inhibitory activity against the T. circumcincta enzyme. Phenotypic screening against T. circumcincta, Haemonchus contortus and C. elegans larval stages identified compounds that caused body morphology phenotypes consistent with the inhibition of proteases involved in cuticle collagen synthesis. These compounds correspondingly inhibited the activity of recombinant T. circumcincta DPY-31, supporting the hypothesis that this enzyme may represent a potentially novel anthelmintic drug target.
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影响因子：
7.3
作者：
Fish, Paul V.;Allan, Gillian A.;Whitlock, Gavin A.
通讯作者：
Whitlock, Gavin A.
影响因子：
64.8
作者：
BODE, W;GOMISRUTH, FX;STOCKER, W
通讯作者：
STOCKER, W
影响因子：
1.5
作者：
Johnstone, IL;Shafi, Y;Barry, JD
通讯作者：
Barry, JD
影响因子：
11.8
作者：
Diemert, David J.;Bethony, Jeffrey M.;Hotez, Peter J.
通讯作者：
Hotez, Peter J.
DOI：
10.1016/0305-0491(89)90360-x
发表时间：
1989-01-01
影响因子：
2.2
作者：
FETTERER, RH
通讯作者：
FETTERER, RH