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Zhijian Cao
College of Life Sciences, Wuhan University, Wuhan 430072, China

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Journal article
Published: 30 August 2021 in Toxins
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Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and β-sheet motifs but also showed remarkable stability at test temperatures from 20–95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases.

ACS Style

Chenhu Qin; Xuhua Yang; Zheng Zuo; Liuting Yang; Fan Yang; Zhijian Cao; Zongyun Chen; Yingliang Wu. BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material. Toxins 2021, 13, 610 .

AMA Style

Chenhu Qin, Xuhua Yang, Zheng Zuo, Liuting Yang, Fan Yang, Zhijian Cao, Zongyun Chen, Yingliang Wu. BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material. Toxins. 2021; 13 (9):610.

Chicago/Turabian Style

Chenhu Qin; Xuhua Yang; Zheng Zuo; Liuting Yang; Fan Yang; Zhijian Cao; Zongyun Chen; Yingliang Wu. 2021. "BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material." Toxins 13, no. 9: 610.

Journal article
Published: 23 July 2021 in Antibiotics
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Scorpion venom is a mixture of bioactive peptides, among which neurotoxins and antimicrobial peptides serve especially vital functions. Scorpion venom peptides in Buthidae species have been well described, but toxic peptides from non-Buthidae species have been under-investigated. Here, an antimicrobial peptide gene, Ctri9594, was cloned and functionally identified from the venom of the scorpion Chaerilus tricostatus. The precursor nucleotide sequence of Ctri9594 is 199 nt in length, including a 43 nt 5′ UTR, 115 nt 3′ UTR and 210 nt ORF. The ORF encodes 69 amino acid residues, containing a 21 aa signal peptide, 14 aa mature peptide, 3 aa C-terminal posttranslational processing signal and 31 aa propeptide. Multiple sequence alignment and evolutionary analyses show that Ctri9594 is an antimicrobial peptide in scorpion venom. The mature peptide of Ctri9594 was chemically synthesized with a purity greater than 95% and a molecular mass of 1484.4 Da. Minimum inhibitory concentrations (MICs) indicate that the synthesized mature peptide of Ctri9594 has inhibitory activity against Gram-positive bacteria (Bacillus thuringensis, Bacillus subtilis, Staphylococcus aureus and Micrococcus luteus) but not Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) or a fungus (Candida albicans). The antimicrobial mechanism of Ctri9594 is inferred to be related to its amphiphilic α-helix structure.

ACS Style

Dangui He; Zhijian Cao; Ruhong Zhang; Wenhua Li. Molecular Cloning and Functional Identification of the Antimicrobial Peptide Gene Ctri9594 from the Venom of the Scorpion Chaerilus tricostatus. Antibiotics 2021, 10, 896 .

AMA Style

Dangui He, Zhijian Cao, Ruhong Zhang, Wenhua Li. Molecular Cloning and Functional Identification of the Antimicrobial Peptide Gene Ctri9594 from the Venom of the Scorpion Chaerilus tricostatus. Antibiotics. 2021; 10 (8):896.

Chicago/Turabian Style

Dangui He; Zhijian Cao; Ruhong Zhang; Wenhua Li. 2021. "Molecular Cloning and Functional Identification of the Antimicrobial Peptide Gene Ctri9594 from the Venom of the Scorpion Chaerilus tricostatus." Antibiotics 10, no. 8: 896.

Journal article
Published: 01 June 2021 in Journal of Allergy and Clinical Immunology
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Tick bites severely threaten human health because they allow the transmission of many deadly pathogens, including viruses, bacteria, protozoa and helminths. Pruritus is a leading symptom of tick bites, but its molecular and neural bases remain elusive. To discover potent drugs and targets for the specific prevention and treatment of tick bite-induced pruritus and arthropod-related itch. We used live-cell calcium imaging, patch-clamp recordings, and genetic ablation and evaluated mouse behavior to investigate the molecular and neural bases of tick bite-induced pruritus. We found that two tick salivary peptides, IPDef1 and IRDef2, induced itch in mice. IPDef1 was further revealed to have a stronger pruritogenic potential than IRDef2 and to induce pruritus in a histamine-independent manner. IPDef1 evoked itch by activating mouse MrgprC11 and human MrgprX1 on dorsal root ganglion (DRG) neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on DRG neurons. Moreover, IPDef1 also activated mouse MrgprB2 and its ortholog human MrgprX2 selectively expressed on mast cells, inducing the release of inflammatory cytokines and driving acute inflammation in mice, although mast cell activation did not contribute to IP-O-induced itch. Our study identifies tick salivary peptides as a new class of pruritogens that initiate itch through MrgprC11/X1-TRPV1 signaling in pruritoceptors. Our work will provide potential drug targets for the prevention and treatment of pruritus induced by the bites or stings of tick and maybe other arthropods.

ACS Style

Xueke Li; Haifeng Yang; Yuewen Han; Shijin Yin; Bingzheng Shen; Yingliang Wu; Wenxin Li; Zhijian Cao. Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors. Journal of Allergy and Clinical Immunology 2021, 147, 2236 -2248.e16.

AMA Style

Xueke Li, Haifeng Yang, Yuewen Han, Shijin Yin, Bingzheng Shen, Yingliang Wu, Wenxin Li, Zhijian Cao. Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors. Journal of Allergy and Clinical Immunology. 2021; 147 (6):2236-2248.e16.

Chicago/Turabian Style

Xueke Li; Haifeng Yang; Yuewen Han; Shijin Yin; Bingzheng Shen; Yingliang Wu; Wenxin Li; Zhijian Cao. 2021. "Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors." Journal of Allergy and Clinical Immunology 147, no. 6: 2236-2248.e16.

Journal article
Published: 26 August 2020 in Antiviral Research
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Arboviruses, especially Dengue virus (DENV) and Zika virus (ZIKV), have been a severe threat to human health in the last few years due to uncontrollable transmission. There are no approved vaccines or clinical drugs available for use to prevent and treat their infections. Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3) were reported to modulate viral entry, but the antiviral function of these modulators was unknown. Here, we reported that ML-SA1, a TRPML agonist, inhibited DENV2 and ZIKV in vitro in a dose-dependent manner. Time-of-drug-addition experiments showed that ML-SA1 mainly restricted viral entry. Moreover, the selective TRPML3 activator SN-2 was found to share a similar antiviral effect against DENV2 and ZIKV, but the specific TRPML1 agonist MK6-83 was not effective. Although ML-SA1 was further revealed to induce autophagy, its antiviral role was independent of autophagy induction. Finally, ML-SA1 was found to inhibit DENV2 and ZIKV by promoting lysosome acidification and protease activity to cause viral degradation. Together, our study identifies two TRPML agonists, ML-SA1 and SN-2, as potent inhibitors of DENV2 and ZIKV, which may lead to the discovery of new candidates against viruses.

ACS Style

Zhiqiang Xia; Luyao Wang; Songryong Li; Wei Tang; Fang Sun; Yingliang Wu; Lixia Miao; Zhijian Cao. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Research 2020, 182, 104922 .

AMA Style

Zhiqiang Xia, Luyao Wang, Songryong Li, Wei Tang, Fang Sun, Yingliang Wu, Lixia Miao, Zhijian Cao. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Research. 2020; 182 ():104922.

Chicago/Turabian Style

Zhiqiang Xia; Luyao Wang; Songryong Li; Wei Tang; Fang Sun; Yingliang Wu; Lixia Miao; Zhijian Cao. 2020. "ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity." Antiviral Research 182, no. : 104922.

Journal article
Published: 17 July 2020 in Biomedicines
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Bradykinin (BK) and bradykinin-related peptides (BRPs), which were identified from a diversity of amphibian skin secretions, exerted contractile and relaxing effects on non-vascular and vascular smooth muscle, respectively. Here, we report a novel bradykinin-related peptide with a molecular mass of 1890.2 Da, RVAGPDKPARISGLSPLR, which was isolated and identified from Ordorrana hejiangensis skin secretions, followed by a C-terminal extension sequence VAPQIV. The biosynthetic precursor-encoding cDNA was cloned by the “shotgun” cloning method, and the novel RR-18 was identified and structurally confirmed by high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Subsequently, the myotropic activity of the synthetic replicate of RR-18 was investigated on the rat bladder, uterus, tail artery and ileum smooth muscle. The peptide was named RR-18 in accordance (R = N-terminal arginine, R = C-terminal arginine, 18 = number of residues). In this study, the synthetic replicates of RR-18 showed no agonist/antagonism of BK-induced rat bladder and uterus smooth muscle contraction. However, it displayed an antagonism of bradykinin-induced rat ileum contraction and arterial smooth muscle relaxation. The EC50 values of BK for ileum and artery, were 214.7 nM and 18.3 nM, respectively. When the tissue was pretreated with the novel peptide, RR-18, at the maximally effective concentration of bradykinin (1 × 10−6 M), bradykinin-induced contraction of the ileum and relaxation of the arterial smooth muscle was reduced by 50–60% and 30–40%, respectively. In conclusion, RR-18 represents novel bradykinin antagonising peptide from amphibian skin secretions. It may provide new insight into possible treatment options for chronic pain and chronic inflammation.

ACS Style

Xiaowei Zhou; Jie Xu; Ruimin Zhong; Chengbang Ma; Mei Zhou; Zhijian Cao; Xinping Xi; Chris Shaw; Tianbao Chen; Lei Wang; Hang Kwok. Pharmacological Effects of a Novel Bradykinin-Related Peptide (RR-18) from the Skin Secretion of the Hejiang Frog (Ordorrana hejiangensis) on Smooth Muscle. Biomedicines 2020, 8, 225 .

AMA Style

Xiaowei Zhou, Jie Xu, Ruimin Zhong, Chengbang Ma, Mei Zhou, Zhijian Cao, Xinping Xi, Chris Shaw, Tianbao Chen, Lei Wang, Hang Kwok. Pharmacological Effects of a Novel Bradykinin-Related Peptide (RR-18) from the Skin Secretion of the Hejiang Frog (Ordorrana hejiangensis) on Smooth Muscle. Biomedicines. 2020; 8 (7):225.

Chicago/Turabian Style

Xiaowei Zhou; Jie Xu; Ruimin Zhong; Chengbang Ma; Mei Zhou; Zhijian Cao; Xinping Xi; Chris Shaw; Tianbao Chen; Lei Wang; Hang Kwok. 2020. "Pharmacological Effects of a Novel Bradykinin-Related Peptide (RR-18) from the Skin Secretion of the Hejiang Frog (Ordorrana hejiangensis) on Smooth Muscle." Biomedicines 8, no. 7: 225.

Review article
Published: 07 June 2020 in Maturitas
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Using Hill's methodology for exploring causality, we aimed to determine in early May 2020 whether evidence supports vitamin D as a biological determinant of COVID-19 outcomes. Vitamin D is a secosteroid hormone theoretically able to reduce COVID-19 risk through regulation of (i) the renin-angiotensin system, (ii) cellular innate and adaptive immunity, and (iii) physical barriers. Inverse associations were found between 25-hydroxyvitamin D concentrations and COVID-19 incidence and mortality. Randomized controlled trials testing vitamin D supplementation in the treatment of COVID-19 are in progress. Positive results in such studies would encourage the use of vitamin D supplements as an adjuvant treatment in COVID-19.

ACS Style

Cédric Annweiler; Zhijian Cao; Jean-Marc Sabatier. Point of view: Should COVID-19 patients be supplemented with vitamin D? Maturitas 2020, 140, 24 -26.

AMA Style

Cédric Annweiler, Zhijian Cao, Jean-Marc Sabatier. Point of view: Should COVID-19 patients be supplemented with vitamin D? Maturitas. 2020; 140 ():24-26.

Chicago/Turabian Style

Cédric Annweiler; Zhijian Cao; Jean-Marc Sabatier. 2020. "Point of view: Should COVID-19 patients be supplemented with vitamin D?" Maturitas 140, no. : 24-26.

Journal article
Published: 08 March 2020 in Viruses
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Interferon-inducible transmembrane proteins (IFITM1/2/3) have been reported to suppress the entry of a wide range of viruses. However, their antiviral functional residues and specific mechanisms are still unclear. Here, we firstly resolved the topology of IFITM1 on the plasma membrane where N-terminus points into the cytoplasm and C-terminus resides extracellularly. Further, KRRK basic residues of IFITM1 locating at 62–67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Similarly, KRRK basic residues of IFITM2/3 also contributed to suppressing ZIKV replication. Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Overall, our study provided topology, antiviral functional residues and the mechanism of interferon-inducible transmembrane proteins.

ACS Style

Fang Sun; Zhiqiang Xia; Yuewen Han; Minjun Gao; Luyao Wang; Yingliang Wu; Jean-Marc Sabatier; Lixia Miao; Zhijian Cao. Topology, Antiviral Functional Residues and Mechanism of IFITM1. Viruses 2020, 12, 295 .

AMA Style

Fang Sun, Zhiqiang Xia, Yuewen Han, Minjun Gao, Luyao Wang, Yingliang Wu, Jean-Marc Sabatier, Lixia Miao, Zhijian Cao. Topology, Antiviral Functional Residues and Mechanism of IFITM1. Viruses. 2020; 12 (3):295.

Chicago/Turabian Style

Fang Sun; Zhiqiang Xia; Yuewen Han; Minjun Gao; Luyao Wang; Yingliang Wu; Jean-Marc Sabatier; Lixia Miao; Zhijian Cao. 2020. "Topology, Antiviral Functional Residues and Mechanism of IFITM1." Viruses 12, no. 3: 295.

Journal article
Published: 17 January 2020 in Antibiotics
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Hepatitis C virus (HCV) infection is a major worldwide health problem which can cause chronic hepatitis, liver fibrosis and hepatocellular carcinoma (HCC). There is still no vaccine to prevent HCV infection. Currently, the clinical treatment of HCV infection mainly relies on the use of direct-acting antivirals (DAAs) which are expensive and have side effects. Here, BmKDfsin3, a scorpion defensin from the venom of Mesobuthus martensii Karsch, is found to dose-dependently inhibit HCV infection at noncytotoxic concentrations and affect viral attachment and post-entry in HCV life cycle. Further experimental results show that BmKDfsin3 not only suppresses p38 mitogen-activated protein kinase (MAPK) activation of HCV-infected Huh7.5.1 cells, but also inhibits p38 activation of Huh7.5.1 cells stimulated by tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) or lipopolysaccharide (LPS). BmKDfsin3 is also revealed to enter into cells. Using an upstream MyD88 dimerization inhibitor ST2345 or kinase IRAK-1/4 inhibitor I, the inhibition of p38 activation represses HCV replication in vitro. Taken together, a scorpion defensin BmKDfsin3 inhibits HCV replication, related to regulated p38 MAPK activation.

ACS Style

Yuting Cheng; Fang Sun; Songryong Li; Minjun Gao; Luyao Wang; Moustafa Sarhan; Mohamed A. Abdel-Rahman; Wenxin Li; Hang Fai Kwok; Yingliang Wu; Zhijian Cao. Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus. Antibiotics 2020, 9, 33 .

AMA Style

Yuting Cheng, Fang Sun, Songryong Li, Minjun Gao, Luyao Wang, Moustafa Sarhan, Mohamed A. Abdel-Rahman, Wenxin Li, Hang Fai Kwok, Yingliang Wu, Zhijian Cao. Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus. Antibiotics. 2020; 9 (1):33.

Chicago/Turabian Style

Yuting Cheng; Fang Sun; Songryong Li; Minjun Gao; Luyao Wang; Moustafa Sarhan; Mohamed A. Abdel-Rahman; Wenxin Li; Hang Fai Kwok; Yingliang Wu; Zhijian Cao. 2020. "Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus." Antibiotics 9, no. 1: 33.

Journal article
Published: 15 October 2019 in Peptides
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Scorpion venom contains diverse bioactive peptides that can recognize and interact with membrane proteins such as ion channels. These natural toxins are believed to be useful tools for exploring the structure and function of ion channels. In this study, we characterized a K+-channel toxin gene, ImKTx96, from the venom gland cDNA library of the scorpion Isometrus maculates. The peptide deduced from the ImKTx96 precursor nucleotide sequence contains a signal peptide of 27 amino acid residues and a mature peptide of 29 residues with three disulfide bridges. Multiple sequence alignment indicated that ImKTx96 is similar with the scorpion toxins that typically target K+-channels. The recombined ImKTx96 peptide (rImKTx96) was expressed in the Escherichia coli system, and purified by GST-affinity chromatography and RP-HPLC. Results from whole-cell patch-clamp experiments revealed that rImKTx96 can inhibit the current of the Kv1.2 ion channel expressed in HEK293 cells. The 3D structure of ImKTx96 was constructed by molecular modeling, and the complex formed by ImKTx96 interacting with the Kv1.2 ion channel was obtained by molecular docking. Based on its structural features and pharmacological functions, ImKTx96 was identified as one member of K+-channel scorpion toxin α-KTx10 group and may be useful as a molecular probe for investigating the structure and function of the Kv1.2 ion channel.

ACS Style

Sipian Li; Shuwen Sunchen; Dangui He; Chenhu Qin; Zheng Zuo; Bingzheng Shen; Zhijian Cao; Wei Hong; Lixia Miao. ImKTx96, a peptide blocker of the Kv1.2 ion channel from the venom of the scorpion Isometrus maculates. Peptides 2019, 123, 170172 .

AMA Style

Sipian Li, Shuwen Sunchen, Dangui He, Chenhu Qin, Zheng Zuo, Bingzheng Shen, Zhijian Cao, Wei Hong, Lixia Miao. ImKTx96, a peptide blocker of the Kv1.2 ion channel from the venom of the scorpion Isometrus maculates. Peptides. 2019; 123 ():170172.

Chicago/Turabian Style

Sipian Li; Shuwen Sunchen; Dangui He; Chenhu Qin; Zheng Zuo; Bingzheng Shen; Zhijian Cao; Wei Hong; Lixia Miao. 2019. "ImKTx96, a peptide blocker of the Kv1.2 ion channel from the venom of the scorpion Isometrus maculates." Peptides 123, no. : 170172.

Review
Published: 29 May 2019 in Molecules
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Scorpion toxins are well-known as the largest potassium channel peptide blocker family. They have been successfully proven to be valuable molecular probes for structural research on diverse potassium channels. The potassium channel pore region, including the turret and filter regions, is the binding interface for scorpion toxins, and structural features from different potassium channels have been identified using different scorpion toxins. According to the spatial orientation of channel turrets with differential sequence lengths and identities, conformational changes and molecular surface properties, the potassium channel turrets can be divided into the following three states: open state with less hindering effects on toxin binding, half-open state or half-closed state with certain effects on toxin binding, and closed state with remarkable effects on toxin binding. In this review, we summarized the diverse structural features of potassium channels explored using scorpion toxin tools and discuss future work in the field of scorpion toxin-potassium channel interactions.

ACS Style

Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes. Molecules 2019, 24, 2045 .

AMA Style

Yonghui Zhao, Zongyun Chen, Zhijian Cao, Wenxin Li, Yingliang Wu. Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes. Molecules. 2019; 24 (11):2045.

Chicago/Turabian Style

Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. 2019. "Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes." Molecules 24, no. 11: 2045.

Conference abstract
Published: 30 January 2019 in Toxicon
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ACS Style

Gaomin Liu; Fangfang Li; Zhongjie Li; Yange Lang; Bingzheng Shen; Yingliang Wu; Wenxin Li; Zhijian Cao. Systematic identification of four antibacterial peptides from the venom of the scorpion Mesobuthus martensii. Toxicon 2019, 158, S11 -S12.

AMA Style

Gaomin Liu, Fangfang Li, Zhongjie Li, Yange Lang, Bingzheng Shen, Yingliang Wu, Wenxin Li, Zhijian Cao. Systematic identification of four antibacterial peptides from the venom of the scorpion Mesobuthus martensii. Toxicon. 2019; 158 ():S11-S12.

Chicago/Turabian Style

Gaomin Liu; Fangfang Li; Zhongjie Li; Yange Lang; Bingzheng Shen; Yingliang Wu; Wenxin Li; Zhijian Cao. 2019. "Systematic identification of four antibacterial peptides from the venom of the scorpion Mesobuthus martensii." Toxicon 158, no. : S11-S12.

Conference abstract
Published: 30 January 2019 in Toxicon
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ACS Style

Yange Lang; Xiaohuan Pi; Zhiyong Di; Qian Zhang; Huijuan Wang; Bingzheng Shen; Fangfang Li; Gaomin Liu; Yao Yu; Xuan Li; Yingliang Wu; Wenxin Li; Zhijian Cao. Molecular characterisation and expression analysis of defensin genes from the scorpion Mesobuthus martensii. Toxicon 2019, 158, S77 .

AMA Style

Yange Lang, Xiaohuan Pi, Zhiyong Di, Qian Zhang, Huijuan Wang, Bingzheng Shen, Fangfang Li, Gaomin Liu, Yao Yu, Xuan Li, Yingliang Wu, Wenxin Li, Zhijian Cao. Molecular characterisation and expression analysis of defensin genes from the scorpion Mesobuthus martensii. Toxicon. 2019; 158 ():S77.

Chicago/Turabian Style

Yange Lang; Xiaohuan Pi; Zhiyong Di; Qian Zhang; Huijuan Wang; Bingzheng Shen; Fangfang Li; Gaomin Liu; Yao Yu; Xuan Li; Yingliang Wu; Wenxin Li; Zhijian Cao. 2019. "Molecular characterisation and expression analysis of defensin genes from the scorpion Mesobuthus martensii." Toxicon 158, no. : S77.

Journal article
Published: 01 January 2019 in Journal of Biological Chemistry
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Viral infections still threaten human health all over the world, and many people die from viral diseases every year. However, there are no effective vaccines or drugs for preventing or managing most viral diseases. Thus, the discovery and development of broad-spectrum antiviral agents remain urgent. Here, we expressed and purified a venom peptide, Ev37, from the scorpion Euscorpiops validus in a prokaryotic system. We found that rEv37 can inhibit dengue virus type 2 (DENV-2), hepatitis C virus (HCV), Zika virus (ZIKV), and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner at noncytotoxic concentrations, but that it has no effect on Sendai virus (SeV) and adenovirus (AdV) infections in vitro. Furthermore, rEv37 alkalized acidic organelles to prevent low pH–dependent fusion of the viral membrane–endosomal membrane, which mainly blocks the release of the viral genome from the endosome to the cytoplasm and then restricts viral late entry. Taken together, our results indicate that the scorpion venom peptide Ev37 is a broad-spectrum antiviral agent with a specific molecular mechanism against viruses undergoing low pH–dependent fusion activation during entry into host cells. We conclude that Ev37 is a potential candidate for development as an antiviral drug.

ACS Style

Fangfang Li; Yange Lang; Zhenglin Ji; Zhiqiang Xia; Yuewen Han; Yuting Cheng; Gaomin Liu; Fang Sun; Yonghui Zhao; Minjun Gao; Zongyun Chen; Yingliang Wu; Wenxin Li; Zhijian Cao. A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles. Journal of Biological Chemistry 2019, 294, 182 -194.

AMA Style

Fangfang Li, Yange Lang, Zhenglin Ji, Zhiqiang Xia, Yuewen Han, Yuting Cheng, Gaomin Liu, Fang Sun, Yonghui Zhao, Minjun Gao, Zongyun Chen, Yingliang Wu, Wenxin Li, Zhijian Cao. A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles. Journal of Biological Chemistry. 2019; 294 (1):182-194.

Chicago/Turabian Style

Fangfang Li; Yange Lang; Zhenglin Ji; Zhiqiang Xia; Yuewen Han; Yuting Cheng; Gaomin Liu; Fang Sun; Yonghui Zhao; Minjun Gao; Zongyun Chen; Yingliang Wu; Wenxin Li; Zhijian Cao. 2019. "A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles." Journal of Biological Chemistry 294, no. 1: 182-194.

Research article
Published: 19 December 2018 in Virologica Sinica
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Dengue virus (DENV) and Zika virus (ZIKV) have spread throughout many countries in the developing world and infect millions of people every year, causing severe harm to human health and the economy. Unfortunately, there are few effective vaccines and therapies available against these viruses. Therefore, the discovery of new antiviral agents is critical. Herein, a scorpion venom peptide (Smp76) characterized from Scorpio maurus palmatus was successfully expressed and purified in Escherichia coli BL21(DE3). The recombinant Smp76 (rSmp76) was found to effectively inhibit DENV and ZIKV infections in a dose-dependent manner in both cultured cell lines and primary mouse macrophages. Interestingly, rSmp76 did not inactivate the viral particles directly but suppressed the established viral infection, similar to the effect of interferon (IFN)-β. Mechanistically, rSmp76 was revealed to upregulate the expression of IFN-β by activating interferon regulatory transcription factor 3 (IRF3) phosphorylation, enhancing the type-I IFN response and inhibiting viral infection. This mechanism is significantly different from traditional virucidal antimicrobial peptides (AMPs). Overall, the scorpion venom peptide Smp76 is a potential new antiviral agent with a unique mechanism involving type-I IFN responses, demonstrating that natural AMPs can enhance immunity by functioning as immunomodulators.

ACS Style

Zhenglin Ji; Fangfang Li; Zhiqiang Xia; Xingchen Guo; Minjun Gao; Fang Sun; Yuting Cheng; Yingliang Wu; Wenxin Li; Syed Abid Ali; Zhijian Cao. The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response. Virologica Sinica 2018, 33, 545 -556.

AMA Style

Zhenglin Ji, Fangfang Li, Zhiqiang Xia, Xingchen Guo, Minjun Gao, Fang Sun, Yuting Cheng, Yingliang Wu, Wenxin Li, Syed Abid Ali, Zhijian Cao. The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response. Virologica Sinica. 2018; 33 (6):545-556.

Chicago/Turabian Style

Zhenglin Ji; Fangfang Li; Zhiqiang Xia; Xingchen Guo; Minjun Gao; Fang Sun; Yuting Cheng; Yingliang Wu; Wenxin Li; Syed Abid Ali; Zhijian Cao. 2018. "The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response." Virologica Sinica 33, no. 6: 545-556.

Review article
Published: 22 November 2018 in Toxicon
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The classical potassium channel inhibitors are toxin peptides from venomous animals, and whether there are peptide inhibitors from other species is an open question. Due to both the independent and interdependent relationships between the spear (peptide inhibitors) and the shield (potassium channels), human defensins were first identified by our group as endogenous potassium channel inhibitors. Encouraged by the discovery of human defensins as potassium channel inhibitors, defensins from invertebrates and fungi were successively found by our group to be potassium channel inhibitors. In addition, a plant defensin was reported to be a potassium channel inhibitor. Since defensins are widely produced by vertebrate, invertebrate, plant and fungi species, the recent work established a new research field on defensin-potassium channel interactions. Here, we review the current work on defensins from vertebrate, invertebrate, plant and fungi species as inhibitors of potassium channels and discuss future work in this research field.

ACS Style

Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. Defensins, a novel type of animal toxin-like potassium channel inhibitor. Toxicon 2018, 157, 101 -105.

AMA Style

Yonghui Zhao, Zongyun Chen, Zhijian Cao, Wenxin Li, Yingliang Wu. Defensins, a novel type of animal toxin-like potassium channel inhibitor. Toxicon. 2018; 157 ():101-105.

Chicago/Turabian Style

Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. 2018. "Defensins, a novel type of animal toxin-like potassium channel inhibitor." Toxicon 157, no. : 101-105.

Journal article
Published: 16 August 2018 in Peptides
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Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to complex interactions between human β-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC50 value of 187.6 ± 25.7 nM; 1 μM hBD4 inhibited 34.0 ± 0.2% of Kv1.3 channel currents. Moreover, 1 μM hBD3 inhibited 50.6 ± 3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human β-defensin family is a novel group of potassium channel inhibitors with diverse types of human β-defensin-potassium channel interactions.

ACS Style

Yonghui Zhao; Zili Xie; Jing Feng; Wenxin Li; Zhijian Cao; Yingliang Wu. Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions. Peptides 2018, 108, 14 -18.

AMA Style

Yonghui Zhao, Zili Xie, Jing Feng, Wenxin Li, Zhijian Cao, Yingliang Wu. Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions. Peptides. 2018; 108 ():14-18.

Chicago/Turabian Style

Yonghui Zhao; Zili Xie; Jing Feng; Wenxin Li; Zhijian Cao; Yingliang Wu. 2018. "Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions." Peptides 108, no. : 14-18.

Journal article
Published: 10 August 2018 in Peptides
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Since there is a symbiotic and competitive relationship between microorganisms in the same ecological niche, fungal defensins have been found to be important resources for antimicrobial peptides. Here, a fungal defensin, triintsin, was characterized in a clinical isolate of Trichophytoninterdigitale from a patient with onychomycosis. The comparison of its genomic and mRNA sequences showed the gene organization and structure of three coding exons separated by two introns. The precursor peptide of triintsin contained 85 amino acid residues, which were composed of three parts including an N-terminal signal domain of 21 residues, a pro-peptide of 47 residues that ended at lysine-arginine and a mature peptide of 38 residues at the C-terminus. The 3D-structure established by homology modeling revealed that triintsin presented a representative typical cysteine-stabilized α-helical and β-sheet fold. The reductive linear peptide of triintsin was obtained by chemical synthesis. After cyclization to form three pairs of disulfide bonds, the oxidative-type peptide displayed broad-spectrum antimicrobial activity against both gram-positive and gram-negative bacteria but also showed anti-fungal activity. Moreover, triintsin can effectively inhibit the growth of clinical strains. Altogether, the peptide is a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity.

ACS Style

Bingzheng Shen; Jinchun Song; Yonghui Zhao; Yaoyun Zhang; Gaomin Liu; Xueke Li; Xingchen Guo; Wenxin Li; Zhijian Cao; Yingliang Wu. Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity. Peptides 2018, 107, 61 -67.

AMA Style

Bingzheng Shen, Jinchun Song, Yonghui Zhao, Yaoyun Zhang, Gaomin Liu, Xueke Li, Xingchen Guo, Wenxin Li, Zhijian Cao, Yingliang Wu. Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity. Peptides. 2018; 107 ():61-67.

Chicago/Turabian Style

Bingzheng Shen; Jinchun Song; Yonghui Zhao; Yaoyun Zhang; Gaomin Liu; Xueke Li; Xingchen Guo; Wenxin Li; Zhijian Cao; Yingliang Wu. 2018. "Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity." Peptides 107, no. : 61-67.

Journal article
Published: 20 June 2018 in Molecules
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The human defensins are recently discovered to inhibit potassium channels, which are classical targets of the animal toxins. Whether other vertebrate defensins are potassium channel inhibitors remains unknown. In this work, we reported that the mouse β-defensin 3 (mBD3) was a novel inhibitor of both endogenous and exogenous potassium channels. The structural analysis showed that mBD3 is the most identical to human Kv1.3 channel-sensitive human β-defensin 2 (hBD2). However, the pharmacological profiles indicated that the recombinant mBD3 (rmBD3) weakly inhibited the mouse and human Kv1.3 channels. Different from the pharmacological features of human β-defensins, mBD3 more selectively inhibited the mouse Kv1.6 and human KCNQ1/KCNE1 channels with IC50 values of 0.6 ± 0.4 μM and 1.2 ± 0.8 μM, respectively. The site directed mutagenesis experiments indicated that the extracellular pore region of mouse Kv1.6 channel was the interaction site of rmBD3. In addition, the minor effect on the channel conductance-voltage relationship curves implied that mBD3 might bind the extracellular transmembrane helices S1-S2 linker and/or S3-S4 linker of mouse Kv1.6 channel. Together, these findings not only revealed mBD3 as a novel inhibitor of both endogenous and exogenous potassium channels, but also provided a clue to investigate the role of mBD3-Kv1.6 channel interaction in the physiological and pathological field in the future.

ACS Style

Yaoyun Zhang; Yonghui Zhao; Hongyue Liu; Weiwei Yu; Fan Yang; Wenhua Li; Zhijian Cao; Yingliang Wu. Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels. Molecules 2018, 23, 1489 .

AMA Style

Yaoyun Zhang, Yonghui Zhao, Hongyue Liu, Weiwei Yu, Fan Yang, Wenhua Li, Zhijian Cao, Yingliang Wu. Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels. Molecules. 2018; 23 (6):1489.

Chicago/Turabian Style

Yaoyun Zhang; Yonghui Zhao; Hongyue Liu; Weiwei Yu; Fan Yang; Wenhua Li; Zhijian Cao; Yingliang Wu. 2018. "Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels." Molecules 23, no. 6: 1489.

Journal article
Published: 01 January 2018 in Peptides
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Scorpion toxins are invaluable pharmacological tools for studying ion channels and potential drugs for channelopathies. The long-chain toxins from scorpion venom with four disulfide bridges exhibit their unusual bioactivity or biotoxicity by acting on the sodium channels. However, the functional properties of most toxins are still unclear due to their tiny amounts in crude venom and their challenging production by chemical and gene engineering techniques. Here, we expressed one of the long-chain α-toxins, BmKM9, found in the venom of the scorpion Buthus martensii Karsch and characterized its pharmacological properties on sodium channels. Unlike previous toxin production, the recombinant BmKM9 (rBmKM9) possessed no additional amino acid residues such as the His-tag and thrombin cleavage site. The refolded toxin could inhibit the inactivation of rNav1.4, hNav1.5 and hNav1.7 sodium channels. Dose-response experiments were further conducted on these channels. The calculated EC50 values were 131.7±6.6nM for rNav1.4, 454.2±50.1nM for hNav1.5 and 30.9±10.3μM for hNav1.7. The channel activation experiments indicated that the rBmKM9 toxin could shift the activation curves of rNav1.4 and hNav1.5 channels toward a more negative direction and present the typical features of a β-toxin. However, instead of the same activation property on sodium channels, the rBmKM9 toxin could result in different inactivation shift capabilities on rNav1.4 and hNav1.5 channels. The V1/2 values of the steady-state inactivation were altered to be more positive for rNav1.4 and more negative for hNav1.5. Moreover, the recovery of the hNav1.5 channel from inactivation was more significantly delayed than that of the rNav1.4 channel by exposure to rBmKM9. Together, these findings highlighted that the rBmKM9 toxin presents the pharmacological properties of both α- and β-toxins, which would increase the challenge to the classical classification of scorpion toxins. Furthermore, the expression method and functional information on sodium channels would promote the potential application of toxins and contribute to further channel structural and functional studies.

ACS Style

Fan Yang; Shuang Liu; Yaoyun Zhang; Chenhu Qin; Lingna Xu; Wenhua Li; Zhijian Cao; Wenxin Li; Yingliang Wu. Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels. Peptides 2018, 99, 153 -160.

AMA Style

Fan Yang, Shuang Liu, Yaoyun Zhang, Chenhu Qin, Lingna Xu, Wenhua Li, Zhijian Cao, Wenxin Li, Yingliang Wu. Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels. Peptides. 2018; 99 ():153-160.

Chicago/Turabian Style

Fan Yang; Shuang Liu; Yaoyun Zhang; Chenhu Qin; Lingna Xu; Wenhua Li; Zhijian Cao; Wenxin Li; Yingliang Wu. 2018. "Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels." Peptides 99, no. : 153-160.

Review
Published: 07 June 2017 in Expert Opinion on Biological Therapy
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Introduction: The effective treatment of autoimmune diseases remains a challenge. Voltage-gated potassium Kv1.3 channels, which are expressed in lymphocytes, are a new therapeutic target for treating autoimmune disease. Consequently, Kv1.3 channel-inhibiting venom-derived peptides are a prospective resource for new drug discovery and clinical application. Area covered: Preclinical and clinical studies have produced a wealth of information on Kv1.3 channel-inhibiting venom-derived peptides, especially from venomous scorpions and sea anemones. This review highlights the advances in screening and design of these peptides with diverse structures and potencies. It focuses on representative strategies for improving peptide selectivity and discusses the preclinical research on those venom-derived peptides as well as their clinical developmental status. Expert opinion: Encouraging results indicate that peptides isolated from the venom of venomous animals are a large resource for discovering immunomodulators that act on Kv1.3 channels. Since the structural diversity of venom-derived peptides determines the variety of their pharmacological activities, the design and optimization of venom-peptides for improved Kv1.3 channel-specificity has been advanced through some representative strategies, such as peptide chemical modification, amino acid residue truncation and binding interface modulation. These advances should further accelerate research, development and the future clinical application of venom-derived peptides selectively targeting Kv1.3 channels.

ACS Style

Bingzheng Shen; Zhijian Cao; Wu Yingliang; Jean-Marc Sabatier; Yingliang Wu. Treating autoimmune disorders with venom-derived peptides. Expert Opinion on Biological Therapy 2017, 17, 1065 -1075.

AMA Style

Bingzheng Shen, Zhijian Cao, Wu Yingliang, Jean-Marc Sabatier, Yingliang Wu. Treating autoimmune disorders with venom-derived peptides. Expert Opinion on Biological Therapy. 2017; 17 (9):1065-1075.

Chicago/Turabian Style

Bingzheng Shen; Zhijian Cao; Wu Yingliang; Jean-Marc Sabatier; Yingliang Wu. 2017. "Treating autoimmune disorders with venom-derived peptides." Expert Opinion on Biological Therapy 17, no. 9: 1065-1075.