Article
Pharmacology & Pharmacy
Yashad Dongol, Phil M. Choi, David T. Wilson, Norelle L. Daly, Fernanda C. Cardoso, Richard J. Lewis
Summary: Through screening Australian spider venom, a peptide inhibiting Na-V channels was isolated, showing effects on various neuronal subtypes and potential for developing subtype selective inhibitors in the future.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Scott P. Fraser, Rustem Onkal, Margaux Theys, Frank Bosmans, Mustafa B. A. Djamgoz
Summary: The neonatal splice variant of Na(V)1.5 (nNa(V)1.5) in breast and colon cancer cells can be pharmacologically distinguished from the adult counterpart (aNa(V)1.5) by specific antibodies and toxins. This finding may contribute to the development of low molecular weight compounds as non-toxic therapeutic drugs for cancers expressing nNa(V)1.5.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
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
Pharmacology & Pharmacy
Steve Peigneur, Cristina da Costa Oliveira, Flavia Cristina de Sousa Fonseca, Kirsten L. McMahon, Alexander Mueller, Olivier Cheneval, Ana Cristina Nogueira Freitas, Hana Starobova, Igor Dimitri Gama Duarte, David J. Craik, Irina Vetter, Maria Elena de Lima, Christina I. Schroeder, Jan Tytgat
Summary: This study aims to downsize larger venom-derived Na-V inhibitors into smaller, more drug-like molecules to bridge the gap between drug leads and candidates. By designing a series of small, stable and novel Na-V probes through molecular engineering, the researchers were able to demonstrate potent analgesic activity and subtype selectivity in vitro and in vivo.
BIOCHEMICAL PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Phuong T. Nguyen, Vladimir Yarov-Yarovoy
Summary: This review focuses on recent progress, current challenges, and future opportunities in developing sodium channel targeting small molecules and peptides as non-addictive therapeutics for treating pain.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Julien Giribaldi, Jean Chemin, Marie Tuifua, Jennifer R. Deuis, Rosanna Mary, Irina Vetter, David T. Wilson, Norelle L. Daly, Christina I. Schroeder, Emmanuel Bourinet, Sebastien Dutertre
Summary: A novel spider toxin, named Pmu1a, was discovered from the venom of Pterinochilus murinus. It has inhibitory activity on both hNa(V)1.7 and hCa(V)3.2 channels, which are therapeutic targets involved in pain pathways. This finding may lead to the development of compounds targeting these channels for chronic pain treatment.
Article
Biochemistry & Molecular Biology
Qing Zhu, Yuzhe Du, Yoshiko Nomura, Rong Gao, Zixuan Cang, Guo-Wei Wei, Dalia Gordon, Michael Gurevitz, James Groome, Ke Dong
Summary: The study indicates that charge substitutions in different structural domains of the sodium channel can enhance the activity of scorpion toxins, particularly the charge reversal substitutions in the voltage-sensing modules of domain III which can facilitate the actions of toxins on IIS4 or IVS4 voltage sensors.
INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2021)
Review
Neurosciences
Gerard A. Marchal, Carol Ann Remme
Summary: In cardiomyocytes, the alpha-subunit of the cardiac voltage-gated Na+ channel (Na(V)1.5) plays a crucial role in the rapid depolarisation of the membrane potential, which is essential for cardiac excitability and electrical propagation. Dysfunctional Na(V)1.5 is associated with a high risk of arrhythmias and sudden cardiac death. However, developing therapeutic interventions targeting Na(V)1.5 has been challenging due to its complexity and diverse roles within the cardiomyocyte.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Biochemistry & Molecular Biology
Pornsawan Khamtorn, Steve Peigneur, Fernanda Gobbi Amorim, Loic Quinton, Jan Tytgat, Sakda Daduang
Summary: This study provides an overview of the molecular diversity of Latrodectus geometricus spider venom through transcriptomic analysis. Several important venom components were identified, and the bioactivity of the venom was investigated using an electrophysiological bioassay. The findings contribute to our understanding of spider venom and can aid in the development of insecticides targeting voltage-gated sodium channels.
Article
Chemistry, Multidisciplinary
Poanna Tran, Theo Crawford, Lotten Ragnarsson, Jennifer R. Deuis, Mehdi Mobli, Simon J. Sharpe, Christina I. Schroeder, Irina Vetter
Summary: Multiple spider venom-derived gating modifier toxins exhibit conformational heterogeneity during purification by RP-HPLC. This phenomenon, often attributed to proline cis/trans isomerization, has also been observed in peptides without a proline residue. Pn3a is one such peptide forming two distinguishable peaks that readily interconvert. In this study, an N-terminal modification of Pn3a allowed the isolation of the conformers and revealed that the earlier-eluting conformer is inactive and disordered, while the later-eluting conformer is active with a rigid structure corresponding to the published structure of Pn3a. The exchange is pH-dependent and may be caused by reversible disruption and formation of intramolecular salt bridges.
Article
Chemistry, Medicinal
Shana L. Geffeney, Jennie Ann Cordingley, Kenyon Mitchell, Charles T. Hanifin
Summary: Multiple animal species have developed resistance to the neurotoxin tetrodotoxin (TTX) by altering the amino acid substitutions in voltage-gated sodium ion channels (VGSCs). This study demonstrates that positionally convergent substitutions of amino acids do not generate similar patterns among TTX-resistant animal lineages, suggesting that flexibility and movement of the protein may play a greater role in causing changes in TTX block.
Article
Biochemistry & Molecular Biology
Pavel Andrei Montero-Dominguez, Gerardo Corzo
Summary: This study investigates the interaction mechanism between scorpion beta-neurotoxins and the human sodium channel. Computational techniques were used to reveal that the toxins bind to specific regions of the sodium channel, leading to voltage sensor entrapment.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
Ada Y. Chen, Bernard R. Brooks, Ana Damjanovic
Summary: In bacterial voltage-gated sodium channels, the passage of ions through the pore is controlled by a selectivity filter (SF) composed of four glutamate residues. This study proposes an alternative mechanism for selectivity, based on ion-triggered shifts in pKa values of SF glutamates. The mechanism suggests that selectivity is achieved through ion-triggered shifts in the protonation state, favoring more conductive states for Na+ ions and less conductive states for K+ ions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Pharmacology & Pharmacy
Agota Csoti, Rosby del Carmen Najera Meza, Ferenc Bogar, Gabor Tajti, Tibor G. Szanto, Zoltan Varga, Georgina B. Gurrola, Gabor K. Toth, Lourival D. Possani, Gyorgy Panyi
Summary: Kv1.3 K+ channels are important in regulating T cell activation and Ca2+ signaling. The novel peptide toxin sVmKTx derived from V. mexicanus smithi shows increased selectivity for Kv1.3 and potential therapeutic application in autoimmune diseases.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Michela Panini, Olga Chiesa, Bartlomiej J. Troczka, Mark Mallott, Gian Carlo Manicardi, Stefano Cassanelli, Filippo Cominelli, Alex Hayward, Emanuele Mazzoni, Chris Bass
Summary: A study reveals a mechanism of insecticide resistance in which previously unavailable recessive resistance alleles are unlocked by transposon-mediated insertional mutagenesis, resulting in insect pests developing resistance to the insecticide bifenthrin.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biology
Tim Lueddecke, Volker Herzig, Bjoern M. Von Reumont, Andreas Vilcinskas
Summary: Spiders have complex venom systems containing diverse components that work synergistically to increase overall potency, enabling them to emerge as one of the most successful animal lineages. Despite being difficult to standardize, the evolution of spider venoms is driven by mechanisms that can be better understood through genome-based studies.
BIOLOGICAL REVIEWS
(2022)
Article
Pharmacology & Pharmacy
Scott P. Fraser, Rustem Onkal, Margaux Theys, Frank Bosmans, Mustafa B. A. Djamgoz
Summary: The neonatal splice variant of Na(V)1.5 (nNa(V)1.5) in breast and colon cancer cells can be pharmacologically distinguished from the adult counterpart (aNa(V)1.5) by specific antibodies and toxins. This finding may contribute to the development of low molecular weight compounds as non-toxic therapeutic drugs for cancers expressing nNa(V)1.5.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Rocio K. Finol-Urdaneta, Rebekah Ziegman, Zoltan Dekan, Jeffrey R. McArthur, Stewart Heitmann, Karen Luna-Ramirez, Han-Shen Tae, Alexander Mueller, Hana Starobova, Yanni K. -Y. Chin, Joshua S. Wingerd, Eivind A. B. Undheim, Ben Cristofori-Armstrong, Adam P. Hill, Volker Herzig, Glenn F. King, Irina Vetter, Lachlan Rash, David J. Adams, Paul F. Alewood
Summary: The venom of the King Baboon spider contains a cysteine-rich peptide that can induce pain by targeting multiple ion channels, leading to hyperexcitability in pain-sensing neurons. This peptide may be an evolutionary adaptation for pain induction in defensive venoms.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Jerome Montnach, Laila Ananda Blomer, Ludivine Lopez, Luiza Filipis, Herve Meudal, Aude Lafoux, Sebastien Nicolas, Duong Chu, Cecile Caumes, Remy Beroud, Chris Jopling, Frank Bosmans, Corinne Huchet, Celine Landon, Marco Canepari, Michel De Waard
Summary: The researchers developed a photoactivatable toxin targeting ion channels and demonstrated its potential in precise control of neuronal channel function through in vitro and in vivo experiments.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Yue Wu, Zhenling Cui, Yen-Hua Huang, Simon J. de Veer, Andrey V. Aralov, Zhong Guo, Shayli V. Moradi, Alexandra O. Hinton, Jennifer R. Deuis, Shaodong Guo, Kai-En Chen, Brett M. Collins, Irina Vetter, Volker Herzig, Alun Jones, Matthew A. Cooper, Glenn F. King, David J. Craik, Kirill Alexandrov, Sergey Mureev
Summary: Advances in peptide and protein therapeutics have increased the demand for rapid and cost-effective polypeptide prototyping. A modified in vitro translation system allows efficient folding of disulfide-rich peptides and proteins in an aggregation-free and thermodynamically controlled environment.
NATURE COMMUNICATIONS
(2022)
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
Biochemistry & Molecular Biology
Fernanda C. Cardoso, Sandy S. Pineda, Volker Herzig, Kartik Sunagar, Naeem Yusuf Shaikh, Ai-Hua Jin, Glenn F. King, Paul F. Alewood, Richard J. Lewis, Sebastien Dutertre
Summary: Australian tree-dwelling funnel-web spiders have venom that induces deadly symptoms and exhibits different venom composition compared to ground-dwelling species. The venom of tree-dwellers strongly modulates human voltage-gated sodium and calcium channels, while also showing potent insecticidal effects. This study contributes to understanding the molecular and pharmacological basis for severe envenomation by Australian tree-dwelling funnel-web spiders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
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
Biochemical Research Methods
Andrew A. Walker, Lynda E. Perkins, Andrea Battisti, Myron P. Zalucki, Glenn F. King
Summary: Ochrogaster lunifer is an Australian caterpillar that has detachable urticating setae with defensive function. These setae can cause inflammation on human skin and equine foetal loss syndrome in gravid horses if accidentally ingested. Transcriptomics and proteomics analysis identified 37 putative toxins, including multiple homologues of honeybee venom peptide secapin and proteins with similarity to odorant binding proteins, arylphorins, and the insect immune modulator Diedel. This study reveals candidate molecules that may contribute to the adverse effects of processionary caterpillar setae on human and animal health.
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
Biochemistry & Molecular Biology
Shahid Hussain, Jolien De Waele, Maxime Lammens, Frank Bosmans
Summary: Comparing the biophysical properties of the Kv channels in honeybees and Asian giant hornets revealed strikingly different gating characteristics. The honeybee Kv channel lacks fast inactivation, while the Asian giant hornet Kv channel displays N-type inactivation.
