Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity.
Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity.
复制标题
小分子去泛素酶抑制剂促进巨噬细胞抗感染能力。
DOI：
10.1371/journal.pone.0104096
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
O'Riordan MX
中科院分区：
文献类型：
--
作者：
Charbonneau ME;Gonzalez-Hernandez MJ;Showalter HD;Donato NJ;Wobus CE;O'Riordan MX
The global spread of anti-microbial resistance requires urgent attention, and diverse alternative strategies have been suggested to address this public health concern. Host-directed immunomodulatory therapies represent one approach that could reduce selection for resistant bacterial strains. Recently, the small molecule deubiquitinase inhibitor WP1130 was reported as a potential anti-infective drug against important human food-borne pathogens, notably Listeria monocytogenes and noroviruses. Utilization of WP1130 itself is limited due to poor solubility, but given the potential of this new compound, we initiated an iterative rational design approach to synthesize new derivatives with increased solubility that retained anti-infective activity. Here, we test a small library of novel synthetic molecules based on the structure of the parent compound, WP1130, for anti-infective activity in vitro. Our studies identify a promising candidate, compound 9, which reduced intracellular growth of L. monocytogenes at concentrations that caused minimal cellular toxicity. Compound 9 itself had no bactericidal activity and only modestly slowed Listeria growth rate in liquid broth culture, suggesting that this drug acts as an anti-infective compound by modulating host-cell function. Moreover, this new compound also showed anti-infective activity against murine norovirus (MNV-1) and human norovirus, using the Norwalk virus replicon system. This small molecule inhibitor may provide a chemical platform for further development of therapeutic deubiquitinase inhibitors with broad-spectrum anti-infective activity.
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影响因子：
11.8
作者：
Hall AJ;Lopman BA;Payne DC;Patel MM;Gastañaduy PA;Vinjé J;Parashar UD
通讯作者：
Parashar UD
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cohen, Philip;Tcherpakov, Marianna
通讯作者：
Tcherpakov, Marianna
影响因子：
3.8
作者：
Duizer, E;Schwab, KJ;Estes, MK
通讯作者：
Estes, MK
影响因子：
3.1
作者：
Burkholder, Kristin M.;Perry, Jeffrey W.;O'Riordan, Mary X. D.
通讯作者：
O'Riordan, Mary X. D.