DC Field | Value | Language |
dc.contributor.author | Lynagh, Timothy | |
dc.contributor.author | Kiontke, Stephan | |
dc.contributor.author | Meyhoff-Madsen, Maria | |
dc.contributor.author | Gless, Bengt H. | |
dc.contributor.author | Johannesen, Jonas | |
dc.contributor.author | Kattelmann, Sabrina | |
dc.contributor.author | Christiansen, Anders | |
dc.contributor.author | Dufva, Martin | |
dc.contributor.author | Laustsen, Andreas H. | |
dc.contributor.author | Devkota, Kanchan | |
dc.contributor.author | Olsen, Christian A. | |
dc.contributor.author | Kuemmel, Daniel | |
dc.contributor.author | Pless, Stephan Alexander | |
dc.contributor.author | Lohse, Brian | |
dc.date.accessioned | 2021-12-23T16:22:21Z | - |
dc.date.available | 2021-12-23T16:22:21Z | - |
dc.date.issued | 2020 | |
dc.identifier.issn | 00222623 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14269 | - |
dc.description.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. | |
dc.description.sponsorship | Carlsberg FoundationCarlsberg Foundation [2013_01_0333]; Lundbeck FoundationLundbeckfonden [R289-20182074, R139-201212390]; Tech Transfer Office, University of Copenhagen; This work was supported by Carlsberg Foundation grant 2013_01_0333 and Lundbeck Foundation grant R289-20182074 to C.A.O., Lundbeck Foundation Fellowship R139-201212390 to S.A.P., and the Tech Transfer Office, University of Copenhagen (to B.L.). We thank Morten Jorgensen, Brian Bentzen, and Jonas Caspersen, at Terrariet, Vissenbjerg, Denmark, for Naja kaouthia venom used in preliminary exploratory studies. | |
dc.language.iso | en | |
dc.publisher | AMER CHEMICAL SOC | |
dc.relation.ispartof | JOURNAL OF MEDICINAL CHEMISTRY | |
dc.subject | Chemistry, Medicinal | |
dc.subject | Pharmacology & Pharmacy | |
dc.title | Peptide Inhibitors of the alpha-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction | |
dc.type | journal article | |
dc.identifier.doi | 10.1021/acs.jmedchem.0c01202 | |
dc.identifier.isi | ISI:000595545900028 | |
dc.description.volume | 63 | |
dc.description.issue | 22 | |
dc.description.startpage | 13709 | |
dc.description.endpage | 13718 | |
dc.contributor.orcid | 0000-0001-5449-0189 | |
dc.contributor.orcid | 0000-0003-0935-3278 | |
dc.contributor.orcid | 0000-0003-4888-4098 | |
dc.contributor.orcid | 0000-0002-2953-8942 | |
dc.contributor.orcid | 0000-0001-6654-114X | |
dc.contributor.orcid | 0000-0001-6918-5574 | |
dc.contributor.researcherid | D-1873-2012 | |
dc.contributor.researcherid | AAZ-6568-2021 | |
dc.identifier.eissn | 15204804 | |
dc.publisher.place | 1155 16TH ST, NW, WASHINGTON, DC 20036 USA | |
dcterms.isPartOf.abbreviation | J. Med. Chem. | |
dcterms.oaStatus | Green Published, hybrid | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | KuDa343 | - |