Structures of drug-specific monoclonal antibodies bound to opioids and nicotine reveal a common mode of binding.

Mice Animals Analgesics, Opioid / therapeutic use Nicotine Antibodies, Monoclonal / chemistry Oxycodone / therapeutic use Morphine / therapeutic use
crystal structure fentanyl ligands mAbs morphine nicotine opioid use disorder oxycodone vaccine

Journal

Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697

Informations de publication

Date de publication:
05 01 2023
Historique:
received: 04 03 2022
revised: 03 08 2022
accepted: 16 11 2022
pubmed: 14 12 2022
medline: 11 1 2023
entrez: 13 12 2022
Statut: ppublish

Résumé

Opioid-related fatal overdoses have reached epidemic proportions. Because existing treatments for opioid use disorders offer limited long-term protection, accelerating the development of newer approaches is critical. Monoclonal antibodies (mAbs) are an emerging treatment strategy that targets and sequesters selected opioids in the bloodstream, reducing drug distribution across the blood-brain barrier, thus preventing or reversing opioid toxicity. We previously identified a series of murine mAbs with high affinity and selectivity for oxycodone, morphine, fentanyl, and nicotine. To determine their binding mechanism, we used X-ray crystallography to solve the structures of mAbs bound to their respective targets, to 2.2 Å resolution or higher. Structural analysis showed a critical convergent hydrogen bonding mode that is dependent on a glutamic acid residue in the mAbs' heavy chain and a tertiary amine of the ligand. Characterizing drug-mAb complexes represents a significant step toward rational antibody engineering and future manufacturing activities to support clinical evaluation.

Identifiants

DOI: 10.1016/j.str.2022.11.008 PMID: 36513069
pubmed: 36513069
pii: S0969-2126(22)00457-9
doi: 10.1016/j.str.2022.11.008
pii:
doi:

Substances chimiques

Analgesics, Opioid 0
Nicotine 6M3C89ZY6R
Antibodies, Monoclonal 0
Oxycodone CD35PMG570
Morphine 76I7G6D29C

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

20-32.e5

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM129325
Pays : United States
Organisme : NIDA NIH HHS
ID : UG3 DA047711
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIH HHS
ID : S10 OD021832
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124169
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA051658
Pays : United States
Organisme : NIDA NIH HHS
ID : UG3 DA057850
Pays : United States

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M. Pravetoni, D.H., and C.B. are inventors of provisional and non-provisional patent applications covering the anti-fentanyl mAbs described herein.

Auteurs

Justas V Rodarte (JV)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Carly Baehr (C)

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.

Dustin Hicks (D)

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.

Tyler L Liban (TL)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Connor Weidle (C)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Peter B Rupert (PB)

Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Rajwana Jahan (R)

Research Triangle Institute International, Research Triangle Park, Durham, NC, USA.

Abigail Wall (A)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Andrew T McGuire (AT)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Roland K Strong (RK)

Basic Science Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Scott Runyon (S)

Research Triangle Institute International, Research Triangle Park, Durham, NC, USA.

Marco Pravetoni (M)

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, School of Medicine, University of Washington, Seattle, WA, USA; Center for Medication Development for Substance Use Disorders and Overdose, University of Washington, Seattle, WA, USA. Electronic address: mprave@uw.edu.

Marie Pancera (M)

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: mpancera@fredhutch.org.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Structures of drug-specific monoclonal...
questionsmedicales.fr › Eucaryotes › Animaux › Structures of drug-specific monoclonal...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Dépresseurs du système nerveux central › Stupéfiants › Analgésiques morphiniques › Structures of drug-specific monoclonal...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Nicotine › Structures of drug-specific monoclonal...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Structures of drug-specific monoclonal...
questionsmedicales.fr › Composés polycycliques › Hydrocarbures aromatiques polycycliques › Phénanthrènes › Morphinanes › Dérivés de la morphine › Codéine › Oxycodone › Structures of drug-specific monoclonal...
questionsmedicales.fr › Composés polycycliques › Hydrocarbures aromatiques polycycliques › Phénanthrènes › Morphinanes › Dérivés de la morphine › Morphine › Structures of drug-specific monoclonal...