当前位置：
X-MOL 学术
›
ACS Infect. Dis.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Characterization of Lead Compounds Targeting the Selenoprotein Thioredoxin Glutathione Reductase for Treatment of Schistosomiasis.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-01-24 , DOI: 10.1021/acsinfecdis.9b00354 Haining Lyu 1 , Pavel A Petukhov 2 , Paul R Banta 1 , Ajit Jadhav 3 , Wendy A Lea 3 , Qing Cheng 4 , Elias S J Arnér 4 , Anton Simeonov 3 , Gregory R J Thatcher 2 , Francesco Angelucci 5 , David L Williams 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-01-24 , DOI: 10.1021/acsinfecdis.9b00354 Haining Lyu 1 , Pavel A Petukhov 2 , Paul R Banta 1 , Ajit Jadhav 3 , Wendy A Lea 3 , Qing Cheng 4 , Elias S J Arnér 4 , Anton Simeonov 3 , Gregory R J Thatcher 2 , Francesco Angelucci 5 , David L Williams 1
Affiliation
|
Schistosomiasis is a widespread human parasitic disease currently affecting over 200 million people. Chemotherapy for schistosomiasis relies exclusively on praziquantel. Although significant advances have been made in recent years to reduce the incidence and intensity of schistosome infections, these gains will be at risk should drug-resistant parasites evolve. Thioredoxin glutathione reductase (TGR) is a selenoprotein of the parasite essential for the survival of schistosomes in the mammalian host. Several high-throughput screening campaigns have identified inhibitors of Schistosoma mansoni TGR. Follow up analyses of select active compounds form the basis of the present study. We identified eight compounds effective against ex vivo worms. Compounds 1-5 are active against all major species and development stages. The ability of these compounds to target immature worms is especially critical because praziquantel is poorly active against this stage. Compounds 1-5, 7, and 8 displayed schistosomicidal activity even after only 1 h incubation with the worms. Compounds 1-4 meet or exceed standards set by the World Health Organization for leads for schistosomiasis therapy activity. The mechanism of TGR inhibition was studied further with wild-type and mutant TGR proteins. Compounds 4-6 were found to induce an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in TGR, leading to the production of superoxide and hydrogen peroxide. Collectively, this effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.
中文翻译：
靶向硒蛋白硫氧还蛋白谷胱甘肽还原酶的铅化合物的表征，用于治疗血吸虫病。
血吸虫病是一种广泛的人类寄生虫病，目前影响超过2亿人。血吸虫病的化学疗法仅依赖吡喹酮。尽管近年来在减少血吸虫感染的发生率和强度方面取得了重大进展，但如果耐药性寄生虫进化，这些收益将处于危险之中。硫氧还蛋白谷胱甘肽还原酶（TGR）是寄生虫的硒蛋白，对哺乳动物血吸虫的存活至关重要。几项高通量筛选活动已鉴定出曼氏血吸虫TGR的抑制剂。对所选活性化合物的后续分析构成了本研究的基础。我们鉴定了八种有效对抗离体蠕虫的化合物。化合物1-5对所有主要物种和发育阶段均具有活性。这些化合物针对未成熟蠕虫的能力尤为关键，因为吡喹酮在此阶段的活性很差。化合物1-5、7和8甚至在与蠕虫温育1小时后仍显示出血吸虫活性。化合物1-4达到或超过世界卫生组织针对血吸虫病治疗活动的铅标准。用野生型和突变型TGR蛋白进一步研究了TGR抑制的机理。发现化合物4-6在TGR中诱导烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性，从而导致超氧化物和过氧化氢的产生。总的来说，这种努力已经确定了几种活性化合物系列，这些活性化合物系列可以作为开发新的血吸虫性化合物的基础。
更新日期：2020-01-24
中文翻译：
靶向硒蛋白硫氧还蛋白谷胱甘肽还原酶的铅化合物的表征，用于治疗血吸虫病。
血吸虫病是一种广泛的人类寄生虫病，目前影响超过2亿人。血吸虫病的化学疗法仅依赖吡喹酮。尽管近年来在减少血吸虫感染的发生率和强度方面取得了重大进展，但如果耐药性寄生虫进化，这些收益将处于危险之中。硫氧还蛋白谷胱甘肽还原酶（TGR）是寄生虫的硒蛋白，对哺乳动物血吸虫的存活至关重要。几项高通量筛选活动已鉴定出曼氏血吸虫TGR的抑制剂。对所选活性化合物的后续分析构成了本研究的基础。我们鉴定了八种有效对抗离体蠕虫的化合物。化合物1-5对所有主要物种和发育阶段均具有活性。这些化合物针对未成熟蠕虫的能力尤为关键，因为吡喹酮在此阶段的活性很差。化合物1-5、7和8甚至在与蠕虫温育1小时后仍显示出血吸虫活性。化合物1-4达到或超过世界卫生组织针对血吸虫病治疗活动的铅标准。用野生型和突变型TGR蛋白进一步研究了TGR抑制的机理。发现化合物4-6在TGR中诱导烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性，从而导致超氧化物和过氧化氢的产生。总的来说，这种努力已经确定了几种活性化合物系列，这些活性化合物系列可以作为开发新的血吸虫性化合物的基础。
京公网安备 11010802027423号