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Prof. Dr. Jan Tytgat is full professor and Head of the Laboratory Toxicology & Pharmacology at the Catholic University of Leuven (KU Leuven) in Belgium. Jan Tytgat’s bibliometric data are h index 50, citations 11,431, and publications >300. He has received several scientific prizes. In 2013, he received the prize for best scientific dissemination from the Flemish Academy of Arts and Sciences. Jan Tytgat is a member of the Superior Health Council of Belgium and a former member of the scientific committee of the Federal Agency for the Safety of the Food Chain in Belgium. He has been President of the European Section of the International Society on Toxinology (IST) and was also appointed as Established Investigator (Pesquisador Visitante Especial) from 2013–2015, in the frame of Science without Borders (Ciências sem Fronteras), from the CNPq agency in Brazil. Jan Tytgat is also leading a forensic toxicology laboratory in Belgium at the request of the Ministry of Justice in his country. He is an expert in the field of drugs, alcohol, doping, and other xenobiotic substances, causing harm to human health and the environment and relevant to sport ethics. In this scope, he is also often contacted by the Belgian and Flemish authorities, national and international agencies/institutes, press, and media for expert opinion, and he is appointed for toxicological reports and risk evaluations. He is also Director of the division "Biopharmaceutical Sciences".
Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (KV10.1) is a voltage‐gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off‐target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure–function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first‐in‐class compounds for the treatment of different cancers.
Žan Toplak; Louise A. Hendrickx; Reham Abdelaziz; Xiaoyi Shi; Steve Peigneur; Tihomir Tomašič; Jan Tytgat; Lucija Peterlin‐Mašič; Luis A. Pardo. Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment. Medicinal Research Reviews 2021, 1 .
AMA StyleŽan Toplak, Louise A. Hendrickx, Reham Abdelaziz, Xiaoyi Shi, Steve Peigneur, Tihomir Tomašič, Jan Tytgat, Lucija Peterlin‐Mašič, Luis A. Pardo. Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment. Medicinal Research Reviews. 2021; ():1.
Chicago/Turabian StyleŽan Toplak; Louise A. Hendrickx; Reham Abdelaziz; Xiaoyi Shi; Steve Peigneur; Tihomir Tomašič; Jan Tytgat; Lucija Peterlin‐Mašič; Luis A. Pardo. 2021. "Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment." Medicinal Research Reviews , no. : 1.
The KV1.3 voltage‐gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting KV1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no KV1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new KV1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward KV1.3. Selectivity of dalatazide (ShK‐186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small‐molecule inhibitors are critically evaluated for their lead‐like characteristics and potential for progression into clinical development. Some small‐molecule inhibitors with well‐defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of KV1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective KV1.3 modulators against this target in the future.
Špela Gubič; Louise A. Hendrickx; Žan Toplak; Maša Sterle; Steve Peigneur; Tihomir Tomašič; Luis A. Pardo; Jan Tytgat; Anamarija Zega; Lucija P. Mašič. Discovery of K V 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges. Medicinal Research Reviews 2021, 41, 2423 -2473.
AMA StyleŠpela Gubič, Louise A. Hendrickx, Žan Toplak, Maša Sterle, Steve Peigneur, Tihomir Tomašič, Luis A. Pardo, Jan Tytgat, Anamarija Zega, Lucija P. Mašič. Discovery of K V 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges. Medicinal Research Reviews. 2021; 41 (4):2423-2473.
Chicago/Turabian StyleŠpela Gubič; Louise A. Hendrickx; Žan Toplak; Maša Sterle; Steve Peigneur; Tihomir Tomašič; Luis A. Pardo; Jan Tytgat; Anamarija Zega; Lucija P. Mašič. 2021. "Discovery of K V 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges." Medicinal Research Reviews 41, no. 4: 2423-2473.
The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2-GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.
Dongchen An; Steve Peigneur; Jan Tytgat. WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels. Biomedicines 2021, 9, 484 .
AMA StyleDongchen An, Steve Peigneur, Jan Tytgat. WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels. Biomedicines. 2021; 9 (5):484.
Chicago/Turabian StyleDongchen An; Steve Peigneur; Jan Tytgat. 2021. "WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels." Biomedicines 9, no. 5: 484.
Background: Oleamide is an essential substance for human health. So, the plants with high oleamide content are great sources for health care products. Objective: This study is conducted to investigate the quality of oleamide in plants and test the bioactivity in the selected two studied species. Methods: The three Ipomoea and five Dillenia species including Ipomoea alba, Ipomoea aquatica and Ipomoea pes-caprae, and Dillenia indica, Dillenia obovata, Dillenia ovata, Dillenia parviflora and Dillenia pentagyna were investigated for the quantity of oleamide by high-performance liquid chromatography. The biological activity test was conducted on the powder formulation of the chosen plants, Dillenia ovata and Dillenia parviflora at a ratio of 30:70, for anti-inflammatory activity ex vivo on a panel of molecular targets through ion channel inhibition including voltage-gated sodium channel, voltage-gated potassium channel, and the cardiac ion as human ether-a-go-go related gene. Results: The results showed that the leaf extracts of I. aquatica and D. ovata gave the highest and subsequent oleamide quantity i.e. 7.52 and 5.17 mg/g, respectively. Out of the Dillenia formulation which contained various compounds, oleamide showed the highest percentages of inhibition at 8.0-20.0%, and 6.2-14.2% in voltage-gated sodium channel, and voltage-gated potassium channel which had slightly lower values than the oleamide standard, and no effect as 0.0% value inhibition in the cardiac ion channel. Conclusion: The Dillenia formulation exhibits anti-inflammatory activity without affecting the heart. Accordingly, the three studied Ipomoea and three studied Dillenia species may be used for the same activity as a single component or formulation with effective solvent for disease treatments.
Unchaleeporn Ameamsri; Arunrat Chaveerach; Runglawan Sudmoon; Tawatchai Tanee; Steve Peigneur; Jan Tytgat. Oleamide in Ipomoea and Dillenia Species and Inflammatory Activity Investigated through Ion Channel Inhibition. Current Pharmaceutical Biotechnology 2021, 22, 254 -261.
AMA StyleUnchaleeporn Ameamsri, Arunrat Chaveerach, Runglawan Sudmoon, Tawatchai Tanee, Steve Peigneur, Jan Tytgat. Oleamide in Ipomoea and Dillenia Species and Inflammatory Activity Investigated through Ion Channel Inhibition. Current Pharmaceutical Biotechnology. 2021; 22 (2):254-261.
Chicago/Turabian StyleUnchaleeporn Ameamsri; Arunrat Chaveerach; Runglawan Sudmoon; Tawatchai Tanee; Steve Peigneur; Jan Tytgat. 2021. "Oleamide in Ipomoea and Dillenia Species and Inflammatory Activity Investigated through Ion Channel Inhibition." Current Pharmaceutical Biotechnology 22, no. 2: 254-261.
(1) Background: The voltage-gated potassium channel KV10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of KV10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC50 value of 3.70 µM against KV10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent KV10.1 inhibitor of the series with an IC50 value of 740 nM, which was potent on the MCF-7 cell line expressing high KV10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent KV10.1 inhibitors. The main problem in the field of KV10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.
Žan Toplak; Louise Hendrickx; Špela Gubič; Štefan Možina; Bojana Žegura; Alja Štern; Matjaž Novak; Xiaoyi Shi; Steve Peigneur; Jan Tytgat; Tihomir Tomašič; Luis Pardo; Lucija Mašič. 3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity. Cancers 2021, 13, 1244 .
AMA StyleŽan Toplak, Louise Hendrickx, Špela Gubič, Štefan Možina, Bojana Žegura, Alja Štern, Matjaž Novak, Xiaoyi Shi, Steve Peigneur, Jan Tytgat, Tihomir Tomašič, Luis Pardo, Lucija Mašič. 3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity. Cancers. 2021; 13 (6):1244.
Chicago/Turabian StyleŽan Toplak; Louise Hendrickx; Špela Gubič; Štefan Možina; Bojana Žegura; Alja Štern; Matjaž Novak; Xiaoyi Shi; Steve Peigneur; Jan Tytgat; Tihomir Tomašič; Luis Pardo; Lucija Mašič. 2021. "3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity." Cancers 13, no. 6: 1244.
Kunitz-type peptides from venomous animals have been known to inhibit different proteinases and also to modulate ion channels and receptors, demonstrating analgesic, anti-inflammatory, anti-histamine and many other biological activities. At present, there is evidence of their neuroprotective effects. We have studied eight Kunitz-type peptides of the sea anemone Heteractis crispa to find molecules with cytoprotective activity in the 6-OHDA-induced neurotoxicity model on neuroblastoma Neuro-2a cells. It has been shown that only five peptides significantly increase the viability of neuronal cells treated with 6-OHDA. The TRPV1 channel blocker, HCRG21, has revealed the neuroprotective effect that could be indirect evidence of TRPV1 involvement in the disorders associated with neurodegeneration. The pre-incubation of Neuro-2a cells with HCRG21 followed by 6-OHDA treatment has resulted in a prominent reduction in ROS production compared the untreated cells. It is possible that the observed effect is due to the ability of the peptide act as an efficient free-radical scavenger. One more leader peptide, InhVJ, has shown a neuroprotective activity and has been studied at concentrations of 0.01–10.0 µM. The target of InhVJ is still unknown, but it was the best of all eight homologous peptides in an absolute cell viability increment on 38% of the control in the 6-OHDA-induced neurotoxicity model. The targets of the other three active peptides remain unknown.
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. Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model. Biomedicines 2021, 9, 283 .
AMA StyleOksana 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. Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model. Biomedicines. 2021; 9 (3):283.
Chicago/Turabian StyleOksana 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. 2021. "Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model." Biomedicines 9, no. 3: 283.
The Tibellus oblongus spider is an active predator that does not spin webs and remains poorly investigated in terms of venom composition. Here, we present a new toxin, named Tbo-IT2, predicted by cDNA analysis of venom glands transcriptome. The presence of Tbo-IT2 in the venom was confirmed by proteomic analyses using the LC-MS and MS/MS techniques. The distinctive features of Tbo-IT2 are the low similarity of primary structure with known animal toxins and the unusual motif of 10 cysteine residues distribution. Recombinant Tbo-IT2 (rTbo-IT2), produced in E. coli using the thioredoxin fusion protein strategy, was structurally and functionally studied. rTbo-IT2 showed insecticidal activity on larvae of the housefly Musca domestica (LD100 200 μg/g) and no activity on the panel of expressed neuronal receptors and ion channels. The spatial structure of the peptide was determined in a water solution by NMR spectroscopy. The Tbo-IT2 structure is a new example of evolutionary adaptation of a well-known inhibitor cystine knot (ICK) fold to 5 disulfide bonds configuration, which determines additional conformational stability and gives opportunities for insectotoxicity and probably some other interesting features.
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. New Insectotoxin from Tibellus Oblongus Spider Venom Presents Novel Adaptation of ICK Fold. Toxins 2021, 13, 29 .
AMA StyleYuliya 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. New Insectotoxin from Tibellus Oblongus Spider Venom Presents Novel Adaptation of ICK Fold. Toxins. 2021; 13 (1):29.
Chicago/Turabian StyleYuliya 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. 2021. "New Insectotoxin from Tibellus Oblongus Spider Venom Presents Novel Adaptation of ICK Fold." Toxins 13, no. 1: 29.
The Kunitz/BPTI peptide family includes unique representatives demonstrating various biological activities. Electrophysiological screening of peptides HCRG1 and HCRG2 from the sea anemone Heteractis crispa on six Kv1.x channel isoforms and insect Shaker IR channel expressed in Xenopus laevis oocytes revealed their potassium channels blocking activity. HCRG1 and HCRG2 appear to be the first Kunitz-type peptides from sea anemones blocking Kv1.3 with IC50 of 40.7 and 29.7 nM, respectively. In addition, peptides mainly vary in binding affinity to the Kv1.2 channels. It was established that the single substitution, Ser5Leu, in the TRPV1 channel antagonist, HCRG21, induces weak blocking activity of Kv1.1, Kv1.2, and Kv1.3. Apparently, for the affinity and selectivity of Kunitz-fold toxins to Kv1.x isoforms, the number and distribution along their molecules of charged, hydrophobic, and polar uncharged residues, as well as the nature of the channel residue at position 379 (Tyr, Val or His) are important. Testing the compounds in a model of acute local inflammation induced by the introduction of carrageenan administration into mice paws revealed that HCRG1 at doses of 0.1–1 mg/kg reduced the volume of developing edema during 24 h, similar to the effect of the nonsteroidal anti-inflammatory drug, indomethacin, at a dose of 5 mg/kg. ELISA analysis of the animals blood showed that the peptide reduced the synthesis of TNF-α, a pro-inflammatory mediator playing a leading role in the development of edema in this model.
Irina Gladkikh; Steve Peigneur; Oksana Sintsova; Ernesto Lopes Pinheiro-Junior; Anna Klimovich; Alexander Menshov; Anatoly Kalinovsky; Marina Isaeva; Margarita Monastyrnaya; Emma Kozlovskaya; Jan Tytgat; Elena Leychenko. Kunitz-Type Peptides from the Sea Anemone Heteractis crispa Demonstrate Potassium Channel Blocking and Anti-Inflammatory Activities. Biomedicines 2020, 8, 473 .
AMA StyleIrina Gladkikh, Steve Peigneur, Oksana Sintsova, Ernesto Lopes Pinheiro-Junior, Anna Klimovich, Alexander Menshov, Anatoly Kalinovsky, Marina Isaeva, Margarita Monastyrnaya, Emma Kozlovskaya, Jan Tytgat, Elena Leychenko. Kunitz-Type Peptides from the Sea Anemone Heteractis crispa Demonstrate Potassium Channel Blocking and Anti-Inflammatory Activities. Biomedicines. 2020; 8 (11):473.
Chicago/Turabian StyleIrina Gladkikh; Steve Peigneur; Oksana Sintsova; Ernesto Lopes Pinheiro-Junior; Anna Klimovich; Alexander Menshov; Anatoly Kalinovsky; Marina Isaeva; Margarita Monastyrnaya; Emma Kozlovskaya; Jan Tytgat; Elena Leychenko. 2020. "Kunitz-Type Peptides from the Sea Anemone Heteractis crispa Demonstrate Potassium Channel Blocking and Anti-Inflammatory Activities." Biomedicines 8, no. 11: 473.
Venoms are a rich source of highly specific toxins, which allow the identification of novel therapeutic targets. We have now applied High Content Screening (HCS) microscopy to identify toxins that modulate pain sensitization signaling in primary sensory neurons of rat and elucidated the underlying mechanism. A set of venoms and fractions thereof were analyzed for their ability to activate type II protein kinase A (PKA‐II) and extracellular signal‐regulated kinases (ERK1/2). We identified MeuNaTxα‐1, a sodium channel‐selective scorpion α‐toxin from Mesobuthus eupeus, which affected both PKA‐II and ERK1/2. Recombinant MeuNaTxα‐1 showed identical activity to the native toxin on mammalian voltage‐gated sodium channels expressed in Xenopus laevis oocytes and induced thermal hyperalgesia in adult mice. The effect of MeuNaTxα‐1 on sensory neurons was dose‐dependent and tetrodotoxin‐sensitive. Application of inhibitors and toxin mutants with altered sodium channel selectivity demonstrated that signaling activation in sensory neurons depends on NaV1.2 isoform. Accordingly, the toxin was more potent in neurons from newborn rats, where NaV1.2 is expressed at a higher level. Our results demonstrate that HCS microscopy‐based monitoring of intracellular signaling is a novel and powerful tool to identify and characterize venoms and their toxins affecting sensory neurons.
Marianne van Cann; Alexey Kuzmenkov; Jörg Isensee; Alexander Andreev‐Andrievskiy; Steve Peigneur; Georgii Khusainov; Antonina Berkut; Jan Tytgat; Alexander Vassilevski; Tim Hucho. Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels. The FEBS Journal 2020, 288, 2418 -2435.
AMA StyleMarianne van Cann, Alexey Kuzmenkov, Jörg Isensee, Alexander Andreev‐Andrievskiy, Steve Peigneur, Georgii Khusainov, Antonina Berkut, Jan Tytgat, Alexander Vassilevski, Tim Hucho. Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels. The FEBS Journal. 2020; 288 (7):2418-2435.
Chicago/Turabian StyleMarianne van Cann; Alexey Kuzmenkov; Jörg Isensee; Alexander Andreev‐Andrievskiy; Steve Peigneur; Georgii Khusainov; Antonina Berkut; Jan Tytgat; Alexander Vassilevski; Tim Hucho. 2020. "Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels." The FEBS Journal 288, no. 7: 2418-2435.
Erythrinian alkaloids ((+)-erythravine and (+)-11-α-hydroxy-erythravine) have been pointed as the main responsible agents for the anticonvulsant and anxiolytic properties of Erythrina mulungu Mart ex Benth. The present work provides a new set of information about the mode of action of these alkaloids by the use of a complementary approach of neurochemical and electrophysiological assays. We propose here that the antiepileptic and anxiolytic properties exhibited by both alkaloids appear not to be related to the inhibition of glutamate binding or GABA uptake, or even to the increase of glutamate uptake or GABA binding, as investigated here by the use of rat cortical synaptosomes. Similarly, and even in a high concentration, (+)-erythravine and (+)-11-α-hydroxy-erythravine did not modulate the main sodium and potassium channel isoforms checked by the use of voltage-clamp studies on Xenopus laevis oocytes. However, unlike (+)-11-α-hydroxy-erythravine, which presented a little effect, it was possible to observe that the (+)-erythravine alkaloid produced a significant inhibitory modulation on α4β2, α4β4 and α7 isoforms of nicotinic acetylcholine receptors also checked by the use of voltage-clamp studies, which could explain at least partially its anxiolytic and anticonvulsant properties. Since (+)-11-α-hydroxy-erythravine and (+)-erythravine modulated nicotinic acetylcholine receptors to different extents, it is possible to reinforce that small differences between the chemical structure of these alkaloids can affect the selectivity and affinity of target-ligand interactions, conferring distinct potency and/or pharmacological properties to them, as previously suggested by differential experimental comparison between different erythrinian alkaloids.
Erica A. Gelfuso; Suelen L. Reis; Daiane S.R. Aguiar; Silmara A. Faggion; Flávia M.M. Gomes; Diogo T. Galan; Steve Peigneur; Ana M.S. Pereira; Márcia R. Mortari; Alexandra O.S. Cunha; Jan Tytgat; Renê O. Beleboni. New insights in the mode of action of (+)-erythravine and (+)-11α-hydroxy-erythravine alkaloids. European Journal of Pharmacology 2020, 885, 173390 .
AMA StyleErica A. Gelfuso, Suelen L. Reis, Daiane S.R. Aguiar, Silmara A. Faggion, Flávia M.M. Gomes, Diogo T. Galan, Steve Peigneur, Ana M.S. Pereira, Márcia R. Mortari, Alexandra O.S. Cunha, Jan Tytgat, Renê O. Beleboni. New insights in the mode of action of (+)-erythravine and (+)-11α-hydroxy-erythravine alkaloids. European Journal of Pharmacology. 2020; 885 ():173390.
Chicago/Turabian StyleErica A. Gelfuso; Suelen L. Reis; Daiane S.R. Aguiar; Silmara A. Faggion; Flávia M.M. Gomes; Diogo T. Galan; Steve Peigneur; Ana M.S. Pereira; Márcia R. Mortari; Alexandra O.S. Cunha; Jan Tytgat; Renê O. Beleboni. 2020. "New insights in the mode of action of (+)-erythravine and (+)-11α-hydroxy-erythravine alkaloids." European Journal of Pharmacology 885, no. : 173390.
Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.
Dongchen An; Steve Peigneur; Louise Antonia Hendrickx; Jan Tytgat. Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products. International Journal of Molecular Sciences 2020, 21, 5064 .
AMA StyleDongchen An, Steve Peigneur, Louise Antonia Hendrickx, Jan Tytgat. Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products. International Journal of Molecular Sciences. 2020; 21 (14):5064.
Chicago/Turabian StyleDongchen An; Steve Peigneur; Louise Antonia Hendrickx; Jan Tytgat. 2020. "Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products." International Journal of Molecular Sciences 21, no. 14: 5064.
Caterpillar envenomation is a global health threat in the 21st century. Every direct or indirect contact with the urticating hairs of a caterpillar results in clinical manifestations ranging from local dermatitis symptoms to potentially life-threatening systemic effects. This is mainly due to the action of bioactive components in the venom that interfere with targets in the human body. The problem is that doctors are limited to relieve symptoms, since an effective treatment is still lacking. Only for Lonomia species an effective antivenom does exist. The health and economical damage are an underestimated problem and will be even more of a concern in the future. For some caterpillar species, the venom composition has been the subject of investigation, while for many others it remains unknown. Moreover, the targets involved in the pathophysiology are poorly understood. This review aims to give an overview of the knowledge we have today on the venom composition of different caterpillar species along with their pharmacological targets. Epidemiology, mode of action, clinical time course and treatments are also addressed. Finally, we briefly discuss the future perspectives that may open the doors for future research in the world of caterpillar toxins to find an adequate treatment.
Andrea Seldeslachts; Steve Peigneur; Jan Tytgat. Caterpillar Venom: A Health Hazard of the 21st Century. Biomedicines 2020, 8, 1 .
AMA StyleAndrea Seldeslachts, Steve Peigneur, Jan Tytgat. Caterpillar Venom: A Health Hazard of the 21st Century. Biomedicines. 2020; 8 (6):1.
Chicago/Turabian StyleAndrea Seldeslachts; Steve Peigneur; Jan Tytgat. 2020. "Caterpillar Venom: A Health Hazard of the 21st Century." Biomedicines 8, no. 6: 1.
The venom of Cupiennius salei is composed of dozens of neurotoxins, with most of them supposed to act on ion channels. Some insecticidal monomeric neurotoxins contain an α-helical part besides their inhibitor cystine knot (ICK) motif (type 1). Other neurotoxins have, besides the ICK motif, an α-helical part of an open loop, resulting in a heterodimeric structure (type 2). Due to their low toxicity, it is difficult to understand the existence of type 2 peptides. Here, we show with the voltage clamp technique in oocytes of Xenopus laevis that a combined application of structural type 1 and type 2 neurotoxins has a much more pronounced cytolytic effect than each of the toxins alone. In biotests with Drosophila melanogaster, the combined effect of both neurotoxins was enhanced by 2 to 3 log units when compared to the components alone. Electrophysiological measurements of a type 2 peptide at 18 ion channel types, expressed in Xenopus laevis oocytes, showed no effect. Microscale thermophoresis data indicate a monomeric/heterodimeric peptide complex formation, thus a direct interaction between type 1 and type 2 peptides, leading to cell death. In conclusion, peptide mergers between both neurotoxins are the main cause for the high cytolytic activity of Cupiennius salei venom.
Benjamin Clémençon; Lucia Kuhn-Nentwig; Nicolas Langenegger; Lukas Kopp; Steve Peigneur; Jan Tytgat; Wolfgang Nentwig; Benjamin P. Lüscher. Neurotoxin Merging: A Strategy Deployed by the Venom of the Spider Cupiennius salei to Potentiate Toxicity on Insects. Toxins 2020, 12, 250 .
AMA StyleBenjamin Clémençon, Lucia Kuhn-Nentwig, Nicolas Langenegger, Lukas Kopp, Steve Peigneur, Jan Tytgat, Wolfgang Nentwig, Benjamin P. Lüscher. Neurotoxin Merging: A Strategy Deployed by the Venom of the Spider Cupiennius salei to Potentiate Toxicity on Insects. Toxins. 2020; 12 (4):250.
Chicago/Turabian StyleBenjamin Clémençon; Lucia Kuhn-Nentwig; Nicolas Langenegger; Lukas Kopp; Steve Peigneur; Jan Tytgat; Wolfgang Nentwig; Benjamin P. Lüscher. 2020. "Neurotoxin Merging: A Strategy Deployed by the Venom of the Spider Cupiennius salei to Potentiate Toxicity on Insects." Toxins 12, no. 4: 250.
The voltage-gated potassium channel Kv1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which Kv1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the Kv1.3 channel. The screening resulted in two compounds inhibiting the Kv1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for Kv1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the Kv1.3 channel and three Kv1.3 mutants, designed to resemble the pore region of Kv1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the Kv1.3 channel, resulting in a 20-fold higher potency for TVS-12.
Louise Antonia Hendrickx; Vladimir Dobričić; Žan Toplak; Steve Peigneur; Lucija Peterlin Mašič; Tihomir Tomašič; Jan Tytgat. Design and characterization of a novel structural class of Kv1.3 inhibitors. Bioorganic Chemistry 2020, 98, 103746 .
AMA StyleLouise Antonia Hendrickx, Vladimir Dobričić, Žan Toplak, Steve Peigneur, Lucija Peterlin Mašič, Tihomir Tomašič, Jan Tytgat. Design and characterization of a novel structural class of Kv1.3 inhibitors. Bioorganic Chemistry. 2020; 98 ():103746.
Chicago/Turabian StyleLouise Antonia Hendrickx; Vladimir Dobričić; Žan Toplak; Steve Peigneur; Lucija Peterlin Mašič; Tihomir Tomašič; Jan Tytgat. 2020. "Design and characterization of a novel structural class of Kv1.3 inhibitors." Bioorganic Chemistry 98, no. : 103746.
Snake venom serine proteases (SVSPs) are complex and multifunctional enzymes, acting primarily on hemostasis. In this work, we report the hitherto unknown inhibitory effect of a SVSP, named collinein-1, isolated from the venom of Crotalus durissus collilineatus, on a cancer-relevant voltage-gated potassium channel (hEAG1). Among 12 voltage-gated ion channels tested, collinein-1 selectively inhibited hEAG1 currents, with a mechanism independent of its enzymatic activity. Corroboratively, we demonstrated that collinein-1 reduced the viability of human breast cancer cell line MCF7 (high expression of hEAG1), but does not affect the liver carcinoma and the non-tumorigenic epithelial breast cell lines (HepG2 and MCF10A, respectively), which present low expression of hEAG1. In order to obtain both functional and structural validation of this unexpected discovery, where an unusually large ligand acts as an inhibitor of an ion channel, a recombinant and catalytically inactive mutant of collinein-1 (His43Arg) was produced and found to preserve its capability to inhibit hEAG1. A molecular docking model was proposed in which Arg79 of the SVSP 99-loop interacts directly with the potassium selectivity filter of the hEAG1 channel.
Johara Boldrini-França; Ernesto Pinheiro-Junior; Steve Peigneur; Manuela Berto Pucca; Felipe Augusto Cerni; Rafael Junqueira Borges; Tássia Rafaella Costa; Sante Emmanuel Imai Carone; Marcos Roberto De Mattos Fontes; Suely Vilela Sampaio; Eliane Candiani Arantes; Jan Tytgat. Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities. Scientific Reports 2020, 10, 1 -11.
AMA StyleJohara Boldrini-França, Ernesto Pinheiro-Junior, Steve Peigneur, Manuela Berto Pucca, Felipe Augusto Cerni, Rafael Junqueira Borges, Tássia Rafaella Costa, Sante Emmanuel Imai Carone, Marcos Roberto De Mattos Fontes, Suely Vilela Sampaio, Eliane Candiani Arantes, Jan Tytgat. Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities. Scientific Reports. 2020; 10 (1):1-11.
Chicago/Turabian StyleJohara Boldrini-França; Ernesto Pinheiro-Junior; Steve Peigneur; Manuela Berto Pucca; Felipe Augusto Cerni; Rafael Junqueira Borges; Tássia Rafaella Costa; Sante Emmanuel Imai Carone; Marcos Roberto De Mattos Fontes; Suely Vilela Sampaio; Eliane Candiani Arantes; Jan Tytgat. 2020. "Beyond hemostasis: a snake venom serine protease with potassium channel blocking and potential antitumor activities." Scientific Reports 10, no. 1: 1-11.
Toxins modulating NaV channels are the most abundant and studied peptide components of sea anemone venom. Three type-II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and RTX-VI, were isolated from the sea anemone Heteractis crispa. RTX-VI has been found to be an unusual analog of RTX-III. The electrophysiological effects of Heteractis toxins on nine NaV subtypes were investigated for the first time. Heteractis toxins mainly affect the inactivation of the mammalian NaV channels expressed in the central nervous system (NaV1.1–NaV1.3, NaV1.6) as well as insect and arachnid channels (BgNaV1, VdNaV1). The absence of Arg13 in the RTX-VI structure does not prevent toxin binding with the channel but it has changed its pharmacological profile and potency. According to computer modeling data, the δ-SHTX-Hcr1f binds within the extracellular region of the rNaV1.2 voltage-sensing domain IV and pore-forming domain I through a network of strong interactions, and an additional fixation of the toxin at the channel binding site is carried out through the phospholipid environment. Our data suggest that Heteractis toxins could be used as molecular tools for NaV channel studies or insecticides rather than as pharmacological agents.
Rimma S. Kalina; Steve Peigneur; Elena A. Zelepuga; Pavel S. Dmitrenok; Aleksandra N. Kvetkina; Natalia Y. Kim; Elena V. Leychenko; Jan Tytgat; Emma P. Kozlovskaya; Margarita M. Monastyrnaya; Irina N. Gladkikh. New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa. Toxins 2020, 12, 44 .
AMA StyleRimma S. Kalina, Steve Peigneur, Elena A. Zelepuga, Pavel S. Dmitrenok, Aleksandra N. Kvetkina, Natalia Y. Kim, Elena V. Leychenko, Jan Tytgat, Emma P. Kozlovskaya, Margarita M. Monastyrnaya, Irina N. Gladkikh. New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa. Toxins. 2020; 12 (1):44.
Chicago/Turabian StyleRimma S. Kalina; Steve Peigneur; Elena A. Zelepuga; Pavel S. Dmitrenok; Aleksandra N. Kvetkina; Natalia Y. Kim; Elena V. Leychenko; Jan Tytgat; Emma P. Kozlovskaya; Margarita M. Monastyrnaya; Irina N. Gladkikh. 2020. "New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa." Toxins 12, no. 1: 44.
CRISPs represent a family of cysteine-rich secretory proteins with molecular mass between 20 and 30 kDa and a highly conserved specific pattern of 16 cysteine residues. In this work, we isolated and characterized a novel CRISP from Bothrops alternatus venom, named BaltCRP, also evaluating its effects on different isoforms of potassium channels (Kv1.1; Kv1.2; Kv1.3; Kv1.4; Kv1.5; Kv2.1; Kv10.1 and Shaker) and on inflammatory processes in vivo. This toxin has a molecular mass of 24.4 kDa and pI around 7.8. Electrophysiological experiments using voltage clamp techniques showed that BaltCRP can affect the currents of Kv1.1; Kv1.3; Kv2.1 and Shaker channels. In addition, BaltCRP induced inflammatory responses characterized by an increase of leukocytes in the peritoneal cavity of mice, also stimulating the production of mediators such IL-6, IL-1β, IL-10, PGE2, PGD2, LTB4 and CysLTs. Altogether, these results demonstrated that BaltCRP can help understand the biological effects evoked by snake venom CRISPs, which could eventually lead to the development of new molecules with therapeutic potential.
Carolina Petri Bernardes; Danilo Luccas Menaldo; Karina Furlani Zoccal; Johara Boldrini-França; Steve Peigneur; Eliane Candiane Arantes; José Cesar Rosa; Lúcia Helena Faccioli; Jan Tytgat; Suely Vilela Sampaio. First report on BaltCRP, a cysteine-rich secretory protein (CRISP) from Bothrops alternatus venom: Effects on potassium channels and inflammatory processes. International Journal of Biological Macromolecules 2019, 140, 556 -567.
AMA StyleCarolina Petri Bernardes, Danilo Luccas Menaldo, Karina Furlani Zoccal, Johara Boldrini-França, Steve Peigneur, Eliane Candiane Arantes, José Cesar Rosa, Lúcia Helena Faccioli, Jan Tytgat, Suely Vilela Sampaio. First report on BaltCRP, a cysteine-rich secretory protein (CRISP) from Bothrops alternatus venom: Effects on potassium channels and inflammatory processes. International Journal of Biological Macromolecules. 2019; 140 ():556-567.
Chicago/Turabian StyleCarolina Petri Bernardes; Danilo Luccas Menaldo; Karina Furlani Zoccal; Johara Boldrini-França; Steve Peigneur; Eliane Candiane Arantes; José Cesar Rosa; Lúcia Helena Faccioli; Jan Tytgat; Suely Vilela Sampaio. 2019. "First report on BaltCRP, a cysteine-rich secretory protein (CRISP) from Bothrops alternatus venom: Effects on potassium channels and inflammatory processes." International Journal of Biological Macromolecules 140, no. : 556-567.
Sea anemone venoms have long been recognised as a rich source of peptides with interesting pharmacological and structural properties. Our recent transcriptomic studies of the Australian sea anemone Actinia tenebrosa have identified a novel 13-residue peptide, U-AITx-Ate1. U-AITx-Ate1 contains a single disulfide bridge and bears no significant homology to previously reported amino acid sequences of peptides from sea anemones or other species. We have produced U-AITx-Ate1 using solid-phase peptide synthesis, followed by oxidative folding and purification of the folded peptide using reversed-phase high-performance liquid chromatography. The solution structure of U-AITx-Ate1 was determined based on two-dimensional nuclear magnetic resonance spectroscopic data. Diffusion-ordered NMR spectroscopy revealed that U-AITx-Ate1 was monomeric in solution. Perturbations in the 1D 1H NMR spectrum of U-AITx-Ate1 in the presence of dodecylphosphocholine micelles together with molecular dynamics simulations indicated an interaction of U-AITx-Ate1 with lipid membranes, although no binding was detected to 100% POPC and 80% POPC: 20% POPG lipid nanodiscs by isothermal titration calorimetry. Functional assays were performed to explore the biological activity profile of U-AITx-Ate1. U-AITx-Ate1 showed no activity in voltage-clamp electrophysiology assays and no change in behaviour and mortality rates in crustacea. Moderate cytotoxic activity was observed against two breast cancer cell lines.
Khaled A. Elnahriry; Dorothy C.C. Wai; Bankala Krishnarjuna; Noha N. Badawy; Balasubramanyam Chittoor; Christopher A. MacRaild; Billy J. Williams-Noonan; Joachim M. Surm; David K. Chalmers; Alan H. Zhang; Steve Peigneur; Mehdi Mobli; Jan Tytgat; Peter Prentis; Raymond S. Norton. Structural and functional characterisation of a novel peptide from the Australian sea anemone Actinia tenebrosa. Toxicon 2019, 168, 104 -112.
AMA StyleKhaled A. Elnahriry, Dorothy C.C. Wai, Bankala Krishnarjuna, Noha N. Badawy, Balasubramanyam Chittoor, Christopher A. MacRaild, Billy J. Williams-Noonan, Joachim M. Surm, David K. Chalmers, Alan H. Zhang, Steve Peigneur, Mehdi Mobli, Jan Tytgat, Peter Prentis, Raymond S. Norton. Structural and functional characterisation of a novel peptide from the Australian sea anemone Actinia tenebrosa. Toxicon. 2019; 168 ():104-112.
Chicago/Turabian StyleKhaled A. Elnahriry; Dorothy C.C. Wai; Bankala Krishnarjuna; Noha N. Badawy; Balasubramanyam Chittoor; Christopher A. MacRaild; Billy J. Williams-Noonan; Joachim M. Surm; David K. Chalmers; Alan H. Zhang; Steve Peigneur; Mehdi Mobli; Jan Tytgat; Peter Prentis; Raymond S. Norton. 2019. "Structural and functional characterisation of a novel peptide from the Australian sea anemone Actinia tenebrosa." Toxicon 168, no. : 104-112.
Sea anemones' venom is rich in peptides acting on different biological targets, mainly on cytoplasmic membranes and ion channels. These animals are also a source of pancreatic α-amylase inhibitors, which have the ability to control the glucose level in the blood and can be used for the treatment of prediabetes and type 2 diabetes mellitus. Recently we have isolated and characterized magnificamide (44 aa, 4770 Da), the major α-amylase inhibitor of the sea anemone Heteractis magnifica mucus, which shares 84% sequence identity with helianthamide from Stichodactyla helianthus. Herein, we report some features in the action of a recombinant analog of magnificamide. The recombinant peptide inhibits porcine pancreatic and human saliva α-amylases with Ki's equal to 0.17 ± 0.06 nM and 7.7 ± 1.5 nM, respectively, and does not show antimicrobial or channel modulating activities. We have concluded that the main function of magnificamide is the inhibition of α-amylases; therefore, its functionally active recombinant analog is a promising agent for further studies as a potential drug candidate for the treatment of the type 2 diabetes mellitus.
Oksana Sintsova; Irina Gladkikh; Aleksandr Kalinovskii; Elena Zelepuga; Margarita Monastyrnaya; Natalia Kim; Lyudmila Shevchenko; Steve Peigneur; Jan Tytgat; Emma Kozlovskaya; Elena Leychenko. Magnificamide, a β-Defensin-Like Peptide from the Mucus of the Sea Anemone Heteractis magnifica, Is a Strong Inhibitor of Mammalian α-Amylases. Marine Drugs 2019, 17, 542 .
AMA StyleOksana Sintsova, Irina Gladkikh, Aleksandr Kalinovskii, Elena Zelepuga, Margarita Monastyrnaya, Natalia Kim, Lyudmila Shevchenko, Steve Peigneur, Jan Tytgat, Emma Kozlovskaya, Elena Leychenko. Magnificamide, a β-Defensin-Like Peptide from the Mucus of the Sea Anemone Heteractis magnifica, Is a Strong Inhibitor of Mammalian α-Amylases. Marine Drugs. 2019; 17 (10):542.
Chicago/Turabian StyleOksana Sintsova; Irina Gladkikh; Aleksandr Kalinovskii; Elena Zelepuga; Margarita Monastyrnaya; Natalia Kim; Lyudmila Shevchenko; Steve Peigneur; Jan Tytgat; Emma Kozlovskaya; Elena Leychenko. 2019. "Magnificamide, a β-Defensin-Like Peptide from the Mucus of the Sea Anemone Heteractis magnifica, Is a Strong Inhibitor of Mammalian α-Amylases." Marine Drugs 17, no. 10: 542.
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types.
Steve Peigneur; Prabha Devi; Andrea Seldeslachts; Samuthirapandian Ravichandran; Loïc Quinton; Jan Tytgat. Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi. Marine Drugs 2019, 17, 535 .
AMA StyleSteve Peigneur, Prabha Devi, Andrea Seldeslachts, Samuthirapandian Ravichandran, Loïc Quinton, Jan Tytgat. Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi. Marine Drugs. 2019; 17 (9):535.
Chicago/Turabian StyleSteve Peigneur; Prabha Devi; Andrea Seldeslachts; Samuthirapandian Ravichandran; Loïc Quinton; Jan Tytgat. 2019. "Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi." Marine Drugs 17, no. 9: 535.