Article
Biochemistry & Molecular Biology
Kirsten L. Mcmahon, Henrik O'Brien, Christina I. Schroeder, Jennifer R. Deuis, Dhananjeyan Venkatachalam, Di Huang, Brad R. Green, Pradip K. Bandyopadhyay, Qing Li, Mark Yandell, Helena Safavi-Hemami, Baldomero M. Olivera, Irina Vetter, Samuel D. Robinson
Summary: This study identified new mu-conotoxins from species of the subgenera Textilia and Afonsoconus and investigated their selectivity at human Na-V channels using RNA-seq and DNA analysis techniques.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Cell Biology
Yun Wu, Manyi Yang, Yubin Li, Wei Zhang, Maojun Zhou
Summary: Conotoxin Lt7b, a novel O-2-superfamily conotoxin, was synthesized and evaluated in this study. It was found that Lt7b could inhibit calcium currents, increase sodium currents, and had no obvious effects on potassium currents. Patch clamp experiments on ion channel subtypes showed that Lt7b could selectively inhibit certain types of currents. Furthermore, Lt7b exhibited no apparent toxicity to cells and increased the pain threshold in mice.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Anuja R. Bony, Jeffrey R. McArthur, Rocio K. Finol-Urdaneta, David J. Adams
Summary: This study is the first to report the potentiation of GIRK channels via allosteric alpha-conotoxin Vc1.1-GABA(B) receptor agonism, leading to decreased neuronal excitability. This finding contributes to the understanding of the analgesic effects of Vc1.1 and baclofen in vivo.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Anuja R. Bony, Jeffrey R. McArthur, Rocio K. Finol-Urdaneta, David J. Adams
Summary: The study shows that analgesic alpha-conotoxins potentiate GIRK channels via GABA(B) receptor-dependent mechanisms, leading to decreased neuronal excitability.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Keri Martinowich, Debamitra Das, Srinidhi Rao Sripathy, Yishan Mai, Rakaia F. Kenney, Brady J. Maher
Summary: This article proposes a potential therapeutic strategy for PTHS by identifying and normalizing dysregulated target genes to restore neuron function and behavioral abnormalities. The study found that inhibiting Na(v)1.8 in PTHS mouse models is effective at restoring normal brain circuit activity and behavior.
MOLECULAR PSYCHIATRY
(2023)
Article
Pharmacology & Pharmacy
Kiran George, Diego Lopez-Mateos, Tarek Mohamed Abd El-Aziz, Yucheng Xiao, Jake Kline, Hong Bao, Syed Raza, James D. Stockand, Theodore R. Cummins, Luca Fornelli, Matthew P. Rowe, Vladimir Yarov-Yarovoy, Ashlee H. Rowe
Summary: This study investigates the gating mechanism of voltage-gated sodium channel Na(V)1.8 and identifies a toxin, NaTx36, produced by Arizona bark scorpions, which can inhibit Na(V)1.8 currents and block pain signals. Mutagenesis experiments reveal critical amino acids involved in the inhibitory effects of NaTx36. Computational modeling provides insights into the interaction between the toxin and the channel.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Chemistry, Medicinal
James R. Groome
Summary: This article reviews the study of marine toxins, particularly on their actions on sodium ion channels regulated by transmembrane voltage and neurotransmitters. The focus is on the diverse conotoxin peptides and their potential applications in evolutionary relationships, biological actions, disease therapy, and understanding the structure of ion channels at the atomic level.
Article
Pharmacology & Pharmacy
Jinqin Chen, Xinhong Liu, Shuo Yu, Jia Liu, Rongfang Chen, Yunxiao Zhang, Ling Jiang, Qiuyun Dai
Summary: Bu8 is a novel omega-conotoxin that is more potent than MVIIA, showing strong analgesic effects in animal pain models with fewer side effects. Its faster binding rate and higher recovery ratios contribute to its lower side effects, and its structure-activity relationships provide new insights for designing CaV2.2 antagonists.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Multidisciplinary Sciences
Philipp Bengel, Nataliya Dybkova, Petros Tirilomis, Shakil Ahmad, Nico Hartmann, Belal A. Mohamed, Miriam Celine Krekeler, Wiebke Maurer, Steffen Pabel, Maximilian Trum, Julian Mustroph, Jan Gummert, Hendrik Milting, Stefan Wagner, Senka Ljubojevic-Holzer, Karl Toischer, Lars S. Maier, Gerd Hasenfuss, Katrin Streckfuss-Bomeke, Samuel Sossalla
Summary: The study reveals the critical role of the sodium channel Na(V)1.8 as a downstream target of CaMKII delta c in arrhythmia formation in heart failure. Knock-out experiments demonstrate the contribution of Na(V)1.8 to the formation of late Na+ current (I-NaL) and its interaction with CaMKII delta c in cardiomyocytes from heart failure patients. The inhibition of Na(V)1.8 reduces diastolic SR-Ca2+ leak and mortality in CaMKII-overexpressing heart failure mice, suggesting a potential prognostic and antiarrhythmic strategy.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Siyi Liu, Cheng Li, Shen You, Qinghui Yan, Sulan Luo, Ying Fu
Summary: In this study, a peptide named Lv32.1 was screened from the conotoxin libraries and its folding conditions were optimized for efficient synthesis. The unique disulfide connectivity and analgesic potential of Lv32.1 were highlighted, providing a foundation for further development as an analgesic candidate.
Article
Cardiac & Cardiovascular Systems
Baozhen Qi, Shimo Dai, Yu Song, Dongli Shen, Fuhai Li, Lanfang Wei, Chunyu Zhang, Zhenning Nie, Jiaxiong Lin, Lidong Cai, Junbo Ge
Summary: This study investigated the role of Na(V)1.8 in ventricular arrhythmias in the AMI model, finding that blockade of NaV1.8 in ganglionated plexi increased the incidence of ventricular arrhythmias in AMI hearts. The study demonstrates an influence of SCN10A/Na(V)1.8 on the regulation of ventricular arrhythmogenesis via modulating ganglionated plexi activity in the AMI model.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Xin Wu, Liang Hong
Summary: Calmodulin (CaM) is a small protein that serves as a ubiquitous signal transducer, regulating neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. Mutations in CaM-binding IQ domain can lead to various diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Jennifer R. Deuis, Lotten Ragnarsson, Samuel D. Robinson, Zoltan Dekan, Lerena Chan, Ai-Hua Jin, Poanna Tran, Kirsten L. McMahon, Shengnan Li, John N. Wood, James J. Cox, Glenn F. King, Volker Herzig, Irina Vetter
Summary: A peptide named β-theraphotoxin-Eo1a was discovered from the venom of the Tanzanian black and olive baboon tarantula, which modulates the function of Na(V)1.8 channels. Eo1a increases the peak current of Na(V)1.8 and causes significant shifts in the voltage-dependence of activation and steady-state fast inactivation.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemical Research Methods
Lina Zhao, Lisa M. Barber, Andrew Hung
Summary: Conotoxins are a family of neurotoxic peptides, with MfVIA being one of them, exhibiting ideal selectivity inhibition on NaV1.8. Molecular dynamics simulations were used to study the effects of various mutations on the structure and dynamics of MfVIA at key residues.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2021)
Article
Biochemical Research Methods
Poanna Tran, Hue N. T. Tran, Kirsten L. McMahon, Jennifer R. Deuis, Lotten Ragnarsson, Alexander Norman, Simon J. Sharpe, Richard J. Payne, Irina Vetter, Christina I. Schroeder
Summary: This study aimed to design new bivalent inhibitors of Na(V)1.7 by combining the pore blocking activity of conotoxins with the gating modifier activity of spider toxins. The potency and selectivity of the resulting bivalent toxins were evaluated by ligating a conotoxin to a spider toxin. The bivalent peptide Pro[LPATG(6)]Sx, resulting from the ligation of ProTx-II and SxIIIC, showed the best combination with conserved potency at hNa(V)1.7.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xiaopeng Zhu, Shuai Wang, Quentin Kaas, Jinpeng Yu, Yong Wu, Peta J. Harvey, Dongting Zhangsun, David J. Craik, Sulan Luo
Summary: The researchers characterized a novel alpha-conotoxin, LvIC, and its analogues to probe structure-activity relationships at the alpha 6 beta 4 nAChR. They found a potent and specific antagonist, [D1G,delta Q14]LvIC, which could potentially serve as a novel molecular probe to explore alpha 6 beta 4 nAChR-related neurophysiological and pharmacological functions.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Junyu Liu, Michael Maxwell, Thom Cuddihy, Theo Crawford, Madeline Bassetti, Cameron Hyde, Steve Peigneur, Jan Tytgat, Eivind A. B. Undheim, Mehdi Mobli
Summary: Receptor avidity through multivalency is difficult to engineer in synthetic molecules, but can be found in natural bivalent antibodies. The discovery of bivalent venom peptides with tandem repeat domains has provided insight into multivalency in biomolecules. ScrepYard, an online resource, assists in identifying SCREP sequences and characterizing this emerging class of biomolecules.
Article
Chemistry, Multidisciplinary
Yan Zhou, Peta J. Harvey, Johannes Koehbach, Lai Yue Chan, Alun Jones, Asa Andersson, Irina Vetter, Thomas Durek, David J. Craik
Summary: In this study, a novel method using asparaginyl endopeptidase (AEP)-mediated cyclization was successfully employed to generate backbone cyclic analogues of MVIIA. These cyclic analogues showed improved pharmaceutical properties, including enhanced stability and inhibition of calcium channels. This study highlights the potential of AEP transpeptidases in cyclizing complex peptides and improving the therapeutic value of conotoxins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemical Research Methods
Poanna Tran, Hue N. T. Tran, Kirsten L. McMahon, Jennifer R. Deuis, Lotten Ragnarsson, Alexander Norman, Simon J. Sharpe, Richard J. Payne, Irina Vetter, Christina I. Schroeder
Summary: This study aimed to design new bivalent inhibitors of Na(V)1.7 by combining the pore blocking activity of conotoxins with the gating modifier activity of spider toxins. The potency and selectivity of the resulting bivalent toxins were evaluated by ligating a conotoxin to a spider toxin. The bivalent peptide Pro[LPATG(6)]Sx, resulting from the ligation of ProTx-II and SxIIIC, showed the best combination with conserved potency at hNa(V)1.7.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemical Research Methods
Qiushi Cao, Cheng Ge, Xuejie Wang, Peta J. Harvey, Zixuan Zhang, Yuan Ma, Xianghong Wang, Xinying Jia, Mehdi Mobli, David J. Craik, Tao Jiang, Jinbo Yang, Zhiqiang Wei, Yan Wang, Shan Chang, Rilei Yu
Summary: With the rise of multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as potential alternatives to traditional antibiotics for treating bacterial infections. However, traditional methods of discovering and designing AMPs are time-consuming and costly. This study utilized deep learning techniques, including sequence generative adversarial nets, bidirectional encoder representations from transformers, and multilayer perceptron, to design and identify AMPs. Six candidate AMPs were then screened and one of them, A-222, showed inhibition against both gram-positive and gram-negative bacteria. Structural analysis and subsequent structure-activity relationship studies led to the design of peptide analogs with increased activity against specific bacteria. Overall, deep learning holds great promise in accelerating the discovery of novel AMPs and could have significant implications in developing new antimicrobial treatments.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Chemistry, Medicinal
Christian R. O. Bartling, Flora Alexopoulou, Sarah Kuschert, Yanni K. -Y. Chin, Xinying Jia, Vita Sereikaite, Dennis Ozcelik, Thomas M. Jensen, Palash Jain, Mads M. Nygaard, Kasper Harpsoe, David E. Gloriam, Mehdi Mobli, Kristian Stromgaard
Summary: Peptides targeting disease-relevant protein-protein interactions have limitations in terms of metabolic stability and membrane permeability. Peptide cyclization, particularly hydrocarbon stapling, offers a valuable approach to develop metabolically stable and cell-permeable cyclic leads with improved affinity and stability. In this study, a comprehensive examination of cyclization strategies led to the identification of cyclic APP dodecamer peptides that target the phosphotyrosine binding domain of Mint2 with significantly improved properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Marie Morin, Mathias Joesson, Conan K. Wang, David J. Craik, Sandie M. Degnan, Bernard M. Degnan
Summary: This study investigates the impact of captivity on the physiology and health of crown-of-thorns starfish by comparing gene expression in wild and captive individuals. The results show significant differences in gene expression between wild and captive starfish, with genes involved in oxidative stress and energy metabolism upregulated in captivity. This suggests that caution should be taken when extrapolating results from captive marine animals to their wild counterparts.
Review
Biochemistry & Molecular Biology
Tristan J. Tyler, Thomas Durek, David J. Craik
Summary: Bioactive peptides are a diverse group of molecules with varied structures and functions. However, their use as drug candidates has been limited due to inherent shortcomings, including short half-lives and poor cell permeability. This review explores the use of molecular engineering to insert bioactive sequences into constrained scaffolds with desired pharmaceutical properties. Specifically, the focus is on cyclic disulfide-rich scaffolds, either naturally derived or engineered, which are intrinsically stable and amenable to sequence modifications, making them privileged frameworks in drug design.
Article
Biochemical Research Methods
Mark A. A. Jackson, Jing Xie, Linh T. T. Nguyen, Xiaohan Wang, Kuok Yap, Peta J. J. Harvey, Edward K. K. Gilding, David J. J. Craik
Summary: Multiple sclerosis (MS) is a debilitating disease that requires prolonged treatment. The experimental therapeutic [T20K]kB1, a mutant of a plant peptide, shows promise for oral dosing and stability due to its cyclic structure. This study demonstrates the production of [T20K]kB1 in the Nicotiana benthamiana plant, providing a sustainable and cost-effective production method for cyclotide-based therapeutics.
TRANSGENIC RESEARCH
(2023)
Article
Immunology
Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Canete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen-Hua Huang, Jonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu
Summary: In antibody responses, mutated germinal center B (BGc) cells are positively selected for reentry or differentiation, with the support of TFH cell-derived signals including CD40 and IL-21. The binding and signaling of IL-21 in BGc cells is reduced compared to non-BGc cells, due to low cellular heparan sulfate (HS) sulfation. Ndst1-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength, and selective desensitization to IL-21 occurs in BGc cells. Therefore, the biochemical regulation of IL-21 availability and signal strength plays a crucial role in GC selection.
SCIENCE IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Despoina Aslanoglou, Andrew M. White, Claudia Draxler, Xaver Kozisek, Zara Farooq, David J. Craik, Peter J. McCormick, Thomas Durek, Christian W. Gruber
Summary: In this study, peptide ligands for MC4R were designed using a peptide drug design approach. The designed peptides fully activated MC4R and recruited beta-arrestin-2 with higher efficacies and potencies than the endogenous alpha-MSH. These findings suggest the potential of these novel peptide ligands in developing safer and more effective antiobesity drugs.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Xinying Jia, Yanni K. -Y. Chin, Alan H. H. Zhang, Theo Crawford, Yifei Zhu, Nicholas L. L. Fletcher, Zihan Zhou, Brett R. R. Hamilton, Martin Stroet, Kristofer J. J. Thurecht, Mehdi Mobli
Summary: The authors report the engineering of self-cyclizing 'autocyclase' proteins to generate macrocyclic peptides and proteins with favorable reaction kinetics for suppressing polymerization. Macrocyclisation of proteins and peptides results in a remarkable increase in structural stability, making cyclic peptides and proteins of great interest in drug discovery. The engineering of a self-cyclising autocyclase protein provides a simple, alternative way to access a vast diversity of macrocyclic biomolecules.
COMMUNICATIONS CHEMISTRY
(2023)
Article
Microbiology
Nicole L. van der Weerden, Kathy Parisi, James A. Mckenna, Brigitte M. Hayes, Peta J. Harvey, Pedro Quimbar, Sean R. Wevrett, Prem K. Veneer, Owen Mccorkelle, Shaily Vasa, Rosemary Guarino, Simon Poon, Yolanda M. Gaspar, Michael J. Baker, David J. Craik, Rob B. Turner, Marc B. Brown, Mark R. Bleackley, Marilyn A. Anderson
Summary: Onychomycosis, or fungal nail infection, can cause pain, discomfort, and psychological and social consequences. Current treatments are limited by poor nail penetration or potential toxicity. Plant defensins, such as Ppdef1, have stable structures and potent antifungal activity, making them promising treatments. Ppdef1 shows excellent activity against a range of fungal pathogens, including Trichophyton rubrum, the major cause of onychomycosis.
Article
Pharmacology & Pharmacy
Yashad Dongol, David T. Wilson, Norelle L. Daly, Fernanda C. Cardoso, Richard J. Lewis
Summary: Structure-function and optimization studies of NaV-inhibiting spider toxins have been conducted to develop selective inhibitors for NaV1.7. This study extends the understanding of the structure-function relationships to include other NaV subtypes, NaV1.2 and NaV1.3. Analogues were designed for improved potency and/or subtype-selectivity, with S7R-E18K-rSsp1a and N14D-P27R-rSsp1a identified as promising leads. The findings highlight the challenge of developing subtype-selective spider toxin inhibitors across multiple NaV subtypes.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Andrew M. White, Cosmin I. Ciotu, Nadine Hochrainer, Natasa Tomasevic, Johannes Koehbach, Richard J. Lewis, Mariana Spetea, Michael J. M. Fischer, David J. Craik, Christian W. Gruber
Summary: In this study, a stable and potent KOR antagonist was developed using cysteine functionalization. The antagonist showed improved selectivity for KOR, and its effectiveness was verified in various cell lines and animal models. This research highlights the value of cysteine stapling in the development of KOR-related drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
