Dual dehydrosqualene/squalene synthase inhibitors: leads for innate immune system-based therapeutics.
Dual dehydrosqualene/squalene synthase inhibitors: leads for innate immune system-based therapeutics.
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DOI：
10.1002/cmdc.201100589
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发表时间：
2012-04
期刊：
影响因子：
3.4
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Lin, Fu-Yang;Zhang, Yonghui;Hensler, Mary;Liu, Yi-Liang;Chow, Ohn A.;Zhu, Wei;Wang, Ke;Pang, Ran;Thienphrapa, Wdee;Nizet, Victor;Oldfield, Eric
关键词：
随着细菌耐药性的迅速上升，[1]人们对开发抗感染治疗的创新方法产生了极大的兴趣。例如，在美国，死于金黄色葡萄球菌感染的人数多于死于艾滋病毒/艾滋病的人数。[2]因此，替代方法是令人感兴趣的，正如最近NRC报告中所讨论的，[1b]这些方法包括靶向毒力因子以及增强先天免疫。在最近的工作[3]中，我们表明用BPH-652阻断类胡萝卜素毒力因子葡萄球菌黄质的形成（1，方案1）使葡萄球菌不具有感染性并且对由活性氧介导的免疫系统清除敏感，并且在其他工作中，[4]我们表明用2抑制中性粒细胞中的角鲨烯生物合成产生抗菌中性粒细胞胞外陷阱或NET。所涉及的靶标，脱氢角鲨烯合酶（CrtM，1）和角鲨烯合酶（SQS，2），都参与类胡萝卜素和甾醇生物合成的第一个关键步骤，即两个法呢基二磷酸分子转化为前角鲨烯二磷酸，图1a。这些发现使我们想到，有可能开发出双重活性的CrtM/SQS抑制剂，同时阻断S。金黄色葡萄球菌毒力因子金黄色葡萄球菌-去除细菌的金色保护壳（图1 B），同时刺激宿主抗微生物NET形成（图1 c）：一种新型的双重靶向免疫治疗方法。我们首先对新的CrtM抑制剂先导物进行了计算机高通量搜索，因为目前的抑制剂如1是较差的NET诱导剂（表1）。同样，使用他汀类药物阻断色素形成是不可行的，因为抑制S.他汀类药物对金黄色葡萄球菌HMG-CoA还原酶的抑制作用比抑制宿主HMG-CoA还原酶的抑制作用大约104倍，这是由于I类/II类酶结构差异较大。[5]我们使用报道的CrtM：1结构
With the rapid rise in bacterial drug-resistance,[1] there is great interest in developing innovative approaches to anti-infective therapy. For example, in the United States, more people die from Staphylococcus aureus infections than die from HIV/AIDS.[2] Alternative approaches are thus of interest, and as discussed in a recent NRC Report,[1b] these include targeting virulence factors, as well as boosting innate immunity. In recent work [3] we showed that blocking formation of the carotenoid virulence factor staphyloxanthin with BPH-652 (1, Scheme 1) rendered staph bacteria non-infective and susceptible to immune system clearance mediated by reactive oxygen species, and in other work,[4] we showed that inhibiting squalene biosynthesis in neutrophils with 2 generated anti-bacterial, neutrophil extra-cellular traps or NETs. The targets involved, dehydrosqualene synthase (CrtM, for 1) and squalene synthase (SQS, for 2), are both involved in the first committed steps in carotenoid and sterol biosynthesis, the conversion of two farnesyl diphosphate molecules to form presqualene diphosphate, Figure 1 a. These findings led us to contemplate that it might be possible to develop dual-activity CrtM/SQS inhibitors that simultaneously block formation of the S. aureus virulence factor staphyloxanthin-removing the golden protective shell (Figure 1 b) of the bacterium, while at the same time stimulating host anti-microbial NET formation (Figure 1 c): a novel, dual-targeting approach to immunotherapy. Here, we report the discovery of such leads.We first carried out an in silico high-throughput search for new CrtM inhibitor leads, since current inhibitors such as 1 are poor NET inducers (Table 1). Likewise, the use of statins to block pigment formation is not feasible since the Ki for inhibition of S. aureus HMG-CoA reductase by statins is~ 104 larger than for inhibition of host HMG-CoA reductase, due to large class I/class II enzyme structural differences.[5] We used the CrtM: 1 structure reported
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DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
2.7
作者：
Larsen, Scott D.;Hester, Matthew R.;Marotti, Keith R.
通讯作者：
Marotti, Keith R.
DOI：
10.1073/pnas.1010907107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Lin, Fu-Yang;Liu, Chia-I;Oldfield, Eric
通讯作者：
Oldfield, Eric
影响因子：
120.7
作者：
Klevens, R. Monina;Morrison, Melissa A.;Fridkin, Scott K.
通讯作者：
Fridkin, Scott K.
影响因子：
56.9
作者：
Liu, Chia-I;Liu, George Y.;Oldfield, Eric
通讯作者：
Oldfield, Eric