Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction. / Lynagh, Timothy; Kiontke, Stephan; Meyhoff-Madsen, Maria; Gless, Bengt H.; Johannesen, Jónas; Kattelmann, Sabrina; Christiansen, Anders; Dufva, Martin; Laustsen, Andreas H.; Devkota, Kanchan; Olsen, Christian A.; Kuemmel, Daniel; Pless, Stephan Alexander; Lohse, Brian.

In: Journal of Medicinal Chemistry, Vol. 63, No. 22, 2020, p. 13709-13718.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lynagh, T, Kiontke, S, Meyhoff-Madsen, M, Gless, BH, Johannesen, J, Kattelmann, S, Christiansen, A, Dufva, M, Laustsen, AH, Devkota, K, Olsen, CA, Kuemmel, D, Pless, SA & Lohse, B 2020, 'Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction', Journal of Medicinal Chemistry, vol. 63, no. 22, pp. 13709-13718. https://doi.org/10.1021/acs.jmedchem.0c01202

APA

Lynagh, T., Kiontke, S., Meyhoff-Madsen, M., Gless, B. H., Johannesen, J., Kattelmann, S., Christiansen, A., Dufva, M., Laustsen, A. H., Devkota, K., Olsen, C. A., Kuemmel, D., Pless, S. A., & Lohse, B. (2020). Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction. Journal of Medicinal Chemistry, 63(22), 13709-13718. https://doi.org/10.1021/acs.jmedchem.0c01202

Vancouver

Lynagh T, Kiontke S, Meyhoff-Madsen M, Gless BH, Johannesen J, Kattelmann S et al. Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction. Journal of Medicinal Chemistry. 2020;63(22):13709-13718. https://doi.org/10.1021/acs.jmedchem.0c01202

Author

Lynagh, Timothy ; Kiontke, Stephan ; Meyhoff-Madsen, Maria ; Gless, Bengt H. ; Johannesen, Jónas ; Kattelmann, Sabrina ; Christiansen, Anders ; Dufva, Martin ; Laustsen, Andreas H. ; Devkota, Kanchan ; Olsen, Christian A. ; Kuemmel, Daniel ; Pless, Stephan Alexander ; Lohse, Brian. / Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 22. pp. 13709-13718.

Bibtex

@article{e1b02b6a24274034816fdd9752558d5a,
title = "Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction",
abstract = "Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake alpha-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure-function characterization, we present simple peptides that bind alpha-cobratoxin (alpha-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented alpha-Cbtx inhibition of nAChRs. We also solved the peptide: alpha-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to alpha-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.",
author = "Timothy Lynagh and Stephan Kiontke and Maria Meyhoff-Madsen and Gless, {Bengt H.} and J{\'o}nas Johannesen and Sabrina Kattelmann and Anders Christiansen and Martin Dufva and Laustsen, {Andreas H.} and Kanchan Devkota and Olsen, {Christian A.} and Daniel Kuemmel and Pless, {Stephan Alexander} and Brian Lohse",
year = "2020",
doi = "10.1021/acs.jmedchem.0c01202",
language = "English",
volume = "63",
pages = "13709--13718",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

RIS

TY - JOUR

T1 - Peptide Inhibitors of the α-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction

AU - Lynagh, Timothy

AU - Kiontke, Stephan

AU - Meyhoff-Madsen, Maria

AU - Gless, Bengt H.

AU - Johannesen, Jónas

AU - Kattelmann, Sabrina

AU - Christiansen, Anders

AU - Dufva, Martin

AU - Laustsen, Andreas H.

AU - Devkota, Kanchan

AU - Olsen, Christian A.

AU - Kuemmel, Daniel

AU - Pless, Stephan Alexander

AU - Lohse, Brian

PY - 2020

Y1 - 2020

N2 - Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake alpha-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure-function characterization, we present simple peptides that bind alpha-cobratoxin (alpha-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented alpha-Cbtx inhibition of nAChRs. We also solved the peptide: alpha-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to alpha-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.

AB - Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake alpha-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure-function characterization, we present simple peptides that bind alpha-cobratoxin (alpha-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented alpha-Cbtx inhibition of nAChRs. We also solved the peptide: alpha-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to alpha-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.

U2 - 10.1021/acs.jmedchem.0c01202

DO - 10.1021/acs.jmedchem.0c01202

M3 - Journal article

C2 - 33143415

VL - 63

SP - 13709

EP - 13718

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -

ID: 256891858