Article
Chemistry, Medicinal
Guangsi Meng, Serdar Kuyucak
Summary: This study aims to improve the affinity and blocking capacity of mu-conotoxin KIIIA for Na(V)1.2 through computational studies. After molecular modeling and simulations on the Na(V)1.2-KIIIA complex, the S5R, S6D, and S13K mutations were identified as the most promising for additional contacts, which could enhance the affinity of KIIIA for Na(V)1.2 and enable complete blocking of the channel.
Article
Biochemistry & Molecular Biology
Xunxun Jian, Yong Wu, Zaoli Mei, Xiaopeng Zhu, Dongting Zhangsun, Sulan Luo
Summary: In the synthesis of conotoxins with multiple disulfide bonds, determining the natural disulfide bond connectivities is challenging due to the diverse connectivities formed during oxidative folding. This study focuses on KIIIA, a mu-conotoxin with potent inhibitory activity against Nav1.2 and Nav1.4. The non-natural connectivity pattern of KIIIA exhibits the highest activity. The study optimized the Fmoc solid-phase synthesis of KIIIA using different strategies, finding that random oxidation and selective strategies can produce high yields and ideal isomers. Distributed oxidation with different protecting groups was also explored, indicating the importance of cleavage order for avoiding disulfide bond scrambling. The activity of synthesized isomers on Nav1.4 was tested, providing valuable guidance for future studies on multi-disulfide-bonded peptides.
Article
Pharmacology & Pharmacy
Ian H. H. Kimball, Phuong T. T. Nguyen, Baldomero M. M. Olivera, Jon T. T. Sack, Vladimir Yarov-Yarovoy
Summary: In this study, the interactions between mu-Conotoxin KIIIA and the human Na(V)1.7 channel were investigated using Rosetta computational modeling and in silico docking. The specific pairwise contacts between KIIIA and hNa(V)1.7 were predicted using RosettaDock and experimentally validated. Comparison with the cryo-EM structure of KIIIA-hNa(V)1.2 revealed important similarities and differences between Na-V channel subtypes, which may have implications for understanding the molecular mechanism of toxin block. The integrative approach used in this study suggests that Rosetta structural predictions can be useful for designing biologics targeting specific Na-V channels.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Angelica Ruelas-Callejas, Manuel B. Aguilar, Rogelio Arteaga-Tlecuitl, Juan Carlos Gomora, Estuardo Lopez-Vera
Summary: Conotoxin sr5a, a highly hydrophobic peptide, was found to selectively block the Na(V)1.5 subtype of sodium channels and modulate the voltage dependence of channel inactivation. This study reveals a potential new molecular interaction for sr5a and provides insights into its pharmacological activity.
Article
Biochemistry & Molecular Biology
Shuang Ju, Yu Zhang, Xijun Guo, Qinghui Yan, Siyi Liu, Bokai Ma, Mei Zhang, Jiaolin Bao, Sulan Luo, Ying Fu
Summary: Conotoxins from marine cone snail venom are valuable drug resources and potential candidates for ovarian cancer treatment.
Article
Food Science & Technology
Kirsten L. McMahon, Hue N. T. Tran, Jennifer R. Deuis, David J. Craik, Irina Vetter, Christina Schroeder
Summary: mu-Conotoxins are peptide inhibitors of Na(V)1.7 channel with potential analgesic effects. Different mu-Conotoxins show varying selectivity towards hNa(V)1.7, with variations in loop 3 residue number and charged residues in this region affecting the selectivity. Additionally, the loop 1 extension in SxIIIC improves the inhibitory potency at hNa(V)1.7 compared to KIIIA.
Review
Chemistry, Medicinal
Francesco Margiotta, Laura Micheli, Clara Ciampi, Carla Ghelardini, J. Michael McIntosh, Lorenzo Di Cesare Mannelli
Summary: This article provides an overview of the main pharmacological features of Conus regius-derived conotoxins, emphasizing on the molecular mechanisms underlying their potential therapeutic effects. Adoptable chemical engineering solutions to improve the pharmacological properties of these conotoxins for future clinical translation are also described.
Article
Food Science & Technology
Jutty Rajan Prashanth, Sebastien Dutertre, Subash Kumar Rai, Richard J. Lewis
Summary: The compartmentalization of the venom gland in cone snails enabled the repurposing of venom peptides to facilitate the dietary shift from vermivory to molluscivory and piscivory.
Article
Neurosciences
Marina Arribas-Blazquez, Dolores Piniella, Luis A. Olivos-Ore, David Bartolome-Martin, Cristiana Leite, Cecilio Gimenez, Antonio R. Artalejo, Francisco Zafra
Summary: The voltage-sensitive sodium channel Na(V)1.1 is regulated by multiple protein kinases, with AKT1 identified as a novel regulator through direct phosphorylation. AKT1 activation leads to decreased Na+ currents and altered inactivation properties, mimicked by its specific activator SC79 and reverted by a selective inhibitor triciribine. This novel mechanism proposes AKT1 as a key regulator in modulating neuronal excitability under physiological and pathological conditions, including epileptogenesis.
Article
Biochemistry & Molecular Biology
Nourhan A. Magdy, Mohamed S. Nafie, Mohamed S. El-Naggar, Mohamed A. Abu El-Regal, Ahmed Z. Abdel Azeiz, Mohamed A. Abdel-Rahman, Mokhtar El-Zawahry
Summary: This study aimed to discover new anticancer drugs from Cone snails' venoms, which are marine natural products with promising biological activities. The venoms from seven cone snails collected from the Red Sea coast were found to have high protein concentrations, and among them, the venoms of C. vexillum (Ma) and C. flavidus showed strong cytotoxic effects against lung and liver cancer cells. The venom of C. flavidus induced apoptotic cell death in HepG2 cells.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
S. W. A. Himaya, Ai-Hua Jin, Brett Hamilton, Subash K. Rai, Paul Alewood, Richard J. Lewis
Summary: By comparing different sections of the venom duct in Pionoconus, it was found that defensive venom is enriched with inhibitory alpha-, omega-, and mu-conotoxins, while predatory venom is rich in excitatory kappa A-conotoxins. Despite their distal expression, kappa A-conotoxins dominate in both predatory and defensive venoms, suggesting they can be selectively expressed in response to predatory or defensive stimuli from the same duct segment. This may indicate an adaptive evolution of kappa A-conotoxins for fish hunting and species radiation in the Pionoconus clade.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Beata Niklas, Milena Jankowska, Dalia Gordon, Laszlo Beress, Maria Stankiewicz, Wieslaw Nowak
Summary: Animal venoms, particularly sea anemone polypeptides, affect neuronal electrical activity by targeting Nav channels. Different toxins exhibit varying potencies in increasing nerve activity, with partial overlap in binding modes between toxins and channels revealed through molecular docking. The higher neuronal activity observed in electrophysiology may be attributed to interactions between anemone toxins and the Nav channel's S4 helix.
Article
Biochemistry & Molecular Biology
Alican Gulsevin, Andrew M. Glazer, Tiffany Shields, Brett M. Kroncke, Dan M. Roden, Jens Meiler
Summary: This study identifies the binding site of veratridine (VTD) on the cardiac sodium ion channel (Na(V)1.5) using docking calculations and high-throughput electrophysiology experiments. The results suggest that VTD binds near the cytoplasmic mouth of the channel pore, potentially indicating an allosteric inactivation mechanism for VTD at Na(V)1.5.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Ena Ivanovic, Jan P. Kucera
Summary: Cardiac ephaptic coupling, mediated by negative electric potentials in intercalated discs, can be influenced by the convoluted structure of the discs. Concentric folds enhance ephaptic interactions, while radial folds attenuate ephaptic interactions.
Article
Neurosciences
Sidharth Tyagi, Nivedita Sarveswaran, Grant P. Higerd-Rusli, Shujun Liu, Fadia B. Dib-Hajj, Stephen G. Waxman, Sulayman D. Dib-Hajj
Summary: Non-addictive treatment for chronic pain is urgently needed. This study investigates the association between Rab6a and Na(V)1.7 and its impact on the trafficking of the channel, providing insights for potential therapeutic interventions.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Unchaleeporn Ameamsri, Arunrat Chaveerach, Runglawan Sudmoon, Tawatchai Tanee, Steve Peigneur, Jan Tytgat
Summary: The study aimed to investigate the oleamide content in different plants and test their bioactivity. Results showed that leaf extracts of Ipomoea aquatica and Dillenia ovata had high oleamide content, while the Dillenia formulation exhibited anti-inflammatory activity.
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
(2021)
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)
Article
Food Science & Technology
Yuliya Korolkova, Ekaterina Maleeva, Alexander Mikov, Anna Lobas, Elizaveta Solovyeva, Mikhail Gorshkov, Yaroslav Andreev, Steve Peigneur, Jan Tytgat, Fedor Kornilov, Vladislav Lushpa, Konstantin Mineev, Sergey Kozlov
Summary: A new toxin named Tbo-IT2 was discovered in the venom of Tibellus oblongus spider, showing low similarity in primary structure with known animal toxins and a unique distribution of 10 cysteine residues. This toxin showed insecticidal activity on housefly larvae and a novel configuration of 5 disulfide bonds, providing insights into evolutionary adaptations for insect toxicity.
Article
Oncology
Zan Toplak, Louise Antonia Hendrickx, Spela Gubic, Stefan Mozina, Bojana Zegura, Alja Stern, Matjaz Novak, Xiaoyi Shi, Steve Peigneur, Jan Tytgat, Tihomir Tomasic, Luis A. Pardo, Lucija Peterlin Masic
Summary: A novel class of inhibitors targeting the voltage-gated potassium channel K(V)10.1 was discovered using a ligand-based drug design method, with the lead compound exhibiting potent inhibition consistent with a gating modifier. However, selectivity against the hERG channel remains a challenge for these inhibitors.
Article
Biochemistry & Molecular Biology
Oksana Sintsova, Irina Gladkikh, Margarita Monastyrnaya, Valentin Tabakmakher, Ekaterina Yurchenko, Ekaterina Menchinskaya, Evgeny Pislyagin, Yaroslav Andreev, Sergey Kozlov, Steve Peigneur, Jan Tytgat, Dmitry Aminin, Emma Kozlovskaya, Elena Leychenko
Summary: Kunitz-type peptides from sea anemone Heteractis crispa have shown neuroprotective effects in 6-OHDA-induced neurotoxicity model, with some peptides exhibiting potent antioxidant properties. Among them, the leader peptide InhVJ demonstrated the best cell viability enhancement. The mechanism and targets of these peptides still require further investigation.
Article
Chemistry, Medicinal
Dongchen An, Ernesto Lopes Pinheiro-Junior, Laszlo Beress, Irina Gladkikh, Elena Leychenko, Eivind A. B. Undheim, Steve Peigneur, Jan Tytgat
Summary: AsKC11, a Kunitz peptide found in the venom of A. sulcata, is the first peptide shown to directly activate neuronal GIRK1/2 channels independent from Gi/o protein activity, without affecting the inward-rectifier potassium channel (IRK1) and with only a minor effect on K(V)1.6 channels. Thus, AsKC11 is a novel activator of GIRK channels resulting in larger K+ currents because of an increased chord conductance.
Article
Chemistry, Medicinal
Ernesto Lopes Pinheiro-Junior, Rimma Kalina, Irina Gladkikh, Elena Leychenko, Jan Tytgat, Steve Peigneur
Summary: Hcr 1b-2, a peptide from the venom of Heteractis crispa, shows a lack of selectivity and targets multiple ion channels, making it an interesting tool for studying ion channels and developing new ion channel ligands.
Article
Biochemistry & Molecular Biology
Prapenpuksiri Rungsa, Steve Peigneur, Nisachon Jangpromma, Sompong Klaynongsruang, Jan Tytgat, Sakda Daduang
Summary: This study investigates the structure-activity relationship of antimicrobial peptides by analyzing the effect of amino acid substitutions and deletion of C-terminal residues. It is found that phenylalanine substitution increases antibacterial activity, while deletions of C-terminal residues decrease antibacterial and hemolytic activity.
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.
Review
Cardiac & Cardiovascular Systems
Anne-Sophie Depuydt, Steve Peigneur, Jan Tytgat
Summary: Pacemaker cells are crucial for the rhythm of the heart, and cardiovascular diseases and arrhythmias are major causes of hospital admissions and sudden death. The prevalence of arrhythmias will increase due to an aging population and risk factors. HCN channels, the molecular correlate of the pacemaker activity, have shown potential as targets for drug development to lower heart rate. However, there is still limited understanding of their pharmacology compared to other ion channels. Ivabradine is currently the only approved drug targeting HCN channels. This review focuses on the pacemaking process in the heart and summarizes current knowledge on HCN channels.
CURRENT CARDIOLOGY REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Aleksandra Kvetkina, Evgeny Pislyagin, Ekaterina Menchinskaya, Ekaterina Yurchenko, Rimma Kalina, Sergei Kozlovskiy, Leonid Kaluzhskiy, Alexander Menshov, Natalia Kim, Steve Peigneur, Jan Tytgat, Alexis Ivanov, Naira Ayvazyan, Elena Leychenko, Dmitry Aminin
Summary: This study investigated the neuroprotective effects of four peptides from sea anemones on Parkinson's disease. The peptides were found to inhibit PD inducers and reduce oxidative stress and inflammation. Furthermore, the study discovered that these peptides interact with the P2X7R channels, which are therapeutic targets for Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Spela Gubic, Louise Antonia Hendrickx, Xiaoyi Shi, Zan Toplak, Stefan Mozina, Kenny M. Van Theemsche, Ernesto Lopes Pinheiro-Junior, Steve Peigneur, Alain J. Labro, Luis A. Pardo, Jan Tytgat, Tihomir Tomasic, Lucija Peterlin Masic
Summary: In this article, a new class of potassium channel inhibitors is described, which selectively inhibits the K(V)1.3 channel and shows potential in inducing apoptosis and inhibiting cell proliferation. The K(V)1.3 channel has recently emerged as a target in cancer therapy. Through structural optimization, a novel K(V)1.3 inhibitor was designed and its potency and selectivity were investigated. The results showed that the new K(V)1.3 inhibitors effectively inhibited cancer cell proliferation and induced apoptosis.
Article
Biochemistry & Molecular Biology
Jessica Matos Kleiz-Ferreira, Hans Bernaerts, Ernesto Lopes Pinheiro-Junior, Steve Peigneur, Russolina Benedeta Zingali, Jan Tytgat
Summary: Coral snake venoms from the Micrurus genus are a diverse collection of components that act on multiple targets. They are mainly composed of phospholipases A(2) and three-finger toxins, which cause neuromuscular blockade. In addition to these major toxin families, minor components also play a significant role in the venom's overall activity. The venoms of five Micrurus species from Brazil were found to act on different types of targets, with potential potassium channel inhibitory activity being a key feature of their envenomation strategy.
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.