The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

Dong, Xiongwei; Zhang, Zhe; Zhao, Jidong; Lei, Juan; Chen, Yuanyuan; Li, Xiang; Chen, Huanhuan; Tian, Junli; Zhang, Dan; Liu, Chunrong; Liu, Changlin

doi:10.1039/c6sc01272h

Cited by 42 publications

(44 citation statements)

References 64 publications

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“…CQ appears to coordinate Cu(II) with moderate affinity (55), and BPS has only been characterized as an Fe(II) chelator but is predicted to form a bis complex with Cu(II) (59). Physical interactions between the chemical compound and the SOD5 protein are likely to play key roles in dictating inhibitor efficacy as well as chelator metal affinities, as has been reported for chemical inhibitors of Cu,Zn-SOD1 (65).…”

Section: Metal Chelators As Chemical Inhibitors Of Copper-only Sod5mentioning

confidence: 85%

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Robinett

Culbertson

Peterson

et al. 2019

Journal of Biological Chemistry

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Edited by F. Peter GuengerichCopper-only superoxide dismutases (SODs) represent a new class of SOD enzymes that are exclusively extracellular and unique to fungi and oomycetes. These SODs are essential for virulence of fungal pathogens in pulmonary and disseminated infections, and we show here an additional role for copper-only SODs in promoting survival of fungal biofilms. The opportunistic fungal pathogen Candida albicans expresses three copperonly SODs, and deletion of one of them, SOD5, eradicated candidal biofilms on venous catheters in a rodent model. Fungal copper-only SODs harbor an irregular active site that, unlike their Cu,Zn-SOD counterparts, contains a copper co-factor unusually open to solvent and lacks zinc for stabilizing copper binding, making fungal copper-only SODs highly vulnerable to metal chelators. We found that unlike mammalian Cu,Zn-SOD1, C. albicans SOD5 indeed rapidly loses its copper to metal chelators such as EDTA, and binding constants for Cu(II) predict that copper-only SOD5 has a much lower affinity for copper than does Cu,Zn-SOD1. We screened compounds with a variety of indications and identified several metal-binding compounds, including the ionophore pyrithione zinc (PZ), that effectively inhibit C. albicans SOD5 but not mammalian Cu,Zn-SOD1. We observed that PZ both acts as an ionophore that promotes uptake of toxic metals and inhibits copper-only SODs. The pros and cons of a vulnerable active site for copper-only SODs and the possible exploitation of this vulnerability in antifungal drug design are discussed.

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Section: Metal Chelators As Chemical Inhibitors Of Copper-only Sod5mentioning

confidence: 85%

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Robinett

Culbertson

Peterson

et al. 2019

Journal of Biological Chemistry

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“…58 Production and enhancement of ROS generation under high-energy radiation is an important factor in cancer radiotherapy. 59 Dihydroethidium (DHE) is a fluorescence probe used to detect the intracellular superoxide anion (O 2 − ), which is the initiator of the free radical chain reaction. Upon receiving highenergy X-ray radiation, high-Z NPs can enhance the O 2 − conversion to generate O 2 − .…”

Section: Activation Of Ros-mediated Signaling Pathwaysmentioning

confidence: 99%

Decorated ultrathin bismuth selenide nanosheets as targeted theranostic agents for in vivo imaging guided cancer radiation therapy

et al. 2017

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An efficient radiotherapeutic agent is synthesized using ultrathin two-dimensional 30-nm-wide and 2-nm-thick Bi 2 Se 3 nanosheets (NSs) as a radiosensitizer. Chitosan (CS) and RGD peptide are employed to enhance the radiotherapy efficiency and biocompatibility. The Bi 2 Se 3 -CS-RGD NSs exhibit excellent targeting ability to αvβ3 integrin-overexpressing cancer cells and potent radiosensitization efficiency with high stability. Detailed in vitro experiments show that the Bi 2 Se 3 -CS-RGD NSs enhance the sensitivity of HeLa cells to X-ray-induced cell death by inhibiting TrxR activities and activating downstream reactive oxygen species-mediated signaling pathways. In vivo experiments using intravenous or intratumor injection demonstrate that the Bi 2 Se 3 -CS-RGD NSs are more efficient tumor growth inhibitors compared to bare Bi 2 Se 3 NSs. The multifunctionality of the NSs enables the use of photoacoustic imaging and magnetic resonance imaging to examine their targeting ability and therapeutic effects, respectively. In addition, the RGD-decorated Bi 2 Se 3 NSs show much better in vivo biocompatibility and can be efficiently expelled from the body after 48 h post injection. This study reveals an effective and safe theranostic agent for next-generation cancer radiotherapy.

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“…To thoroughly understand the effects of the specific SOD1 inhibition with the inhibitor LD100 (Figure 1(a)) on the expression of the global proteome in the cancer cell, we first performed the global mRNA sequencing on the HeLa cells treated with and without 50 μ M LD100, and SOD1 activity was validated to be reduced by approximate 85% by this inhibitor [44]. The SOD1 knockdown group was set for comparison, and both the expression and protein levels of SOD1 were validated to be reduced by >80% in the SOD1 siRNA-treated HeLa cells after interference for 24 h relative to control (Figures S1(a) and S1(b)).…”

Section: Resultsmentioning

confidence: 99%

“…After mapping the reads of all mRNA sequencing samples in HeLa cells to the reference genome (Table S1), the total of 4513 differentially expressed genes (DEGs) was identified in the knockdown group and the total of 2650 DEGs was identified in the SOD1 inhibition group compared to the control group (Figure 1(b) and Figure S1(f)). The DEGs in the SOD1 knockdown group were much more than those in the SOD1 inhibition group, as SOD1 had been proposed to act as a nuclear transcription factor [26] and its specific inhibition altered only the intracellular ROS levels [44] and might not alter its activity as a nuclear transcription factor. However, 1145 overlapped DEGs in these two groups indicated that the expression of these genes was mainly regulated by the alterations of ROS levels resulted from the reduction of SOD1 activity (Figure 1(c)).…”

Section: Resultsmentioning

confidence: 99%

“…These observations indicate that lack of specific SOD1 inhibitors is a hindrance that needs to be overcome in the exploration of the specific interruption of H 2 O 2 signaling. Based on the active site structure and catalytic mechanism of SOD1, we designed an efficient copper-chelating and specific SOD1 inhibitor, LD100 [44]. Cell experiments indicated that it did not impact the activity of other copper proteins and enzymes, and its IC 50 reaches at a nanomolar scale in the inhibition of intracellular SOD1 activity.…”

Section: Introductionmentioning

confidence: 99%

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The Specific Inhibition of SOD1 Selectively Promotes Apoptosis of Cancer Cells via Regulation of the ROS Signaling Network

Chen

Zhao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Multiple signaling pathways including ERK, PI3K-Akt, and NF-κB, which are essential for onset and development of cancer, can be activated by intracellularly sustained high levels of H2O2 provided by elevated activity and expression of copper/zinc superoxide dismutase (SOD1) that catalyzes the dismutation of O2•− into H2O2. Here, tests performed by the utilization of our designed specific SOD1 inhibitor LD100 on cancer and normal cells reveal that the signaling pathways and their crosstalk to support cancer cell growth are repressed, but the signaling pathways to promote cancer cell cycle arrest and apoptosis are stimulated by specific SOD1 inhibition-mediated ROS changes. These regulated pathways constitute an ROS signaling network that determines the fate of cancer cells. This ROS signaling network is also regulated in SOD1 knockdown cells. These findings might facilitate disclosure of action mechanisms by copper-chelating anticancer agents and design of SOD1-targeting and ROS signaling pathway-interfering anticancer small molecules.

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The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

Abstract: Based on the active site structure and catalytic mechanism of SOD1, we developed a new type of efficient and specific SOD1 inhibitor which can directly change the intracellular levels of H2O2 and O2˙–.

Cited by 42 publications

References 64 publications

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Decorated ultrathin bismuth selenide nanosheets as targeted theranostic agents for in vivo imaging guided cancer radiation therapy

The Specific Inhibition of SOD1 Selectively Promotes Apoptosis of Cancer Cells via Regulation of the ROS Signaling Network

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