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

Justas V. Rodarte, Carly Baehr, Dustin Hicks, Tyler L. Liban, Connor Weidle, Peter B. Rupert, Rajwana Jahan, Abigail Wall, Andrew T. McGuire, Roland K. Strong, Scott Runyon, Marco Pravetoni, Marie Pancera

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20-32.e5
JournalStructure
Volume31
Issue number1
DOIs
StatePublished - Jan 5 2023

Bibliographical note

Funding Information:
We are particularly grateful to Julian Simon and Nick Hurlburt for their help in reviewing and preparing this paper and its figures, and to Leo Stamatatos for use of laboratory space and equipment. We are grateful to Mark LeSage for the gift of NIC311 IgG. We thank the J.B. Pendleton Charitable Trust for its generous support of Formulatrix robotic instruments. This work was funded by grants UG3 DA047711 and U01 DA051658 from the National Institutes of Health (NIH) and the National Institute on Drug Abuse (NIDA) (M. Pravetoni and M. Pancera). Some results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source, under US Department of Energy, Office of Biological and Environmental Research contract DE-AC02-06CH11357. Further work was performed at the Berkeley Center for Structural Biology, which is supported in part by the Howard Hughes Medical Institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under contract no. DE-AC02-05CH11231. The Pilatus detector on 5.0.1. was funded under NIH grant S10 OD021832. The ALS-ENABLE beamlines are supported in part by the NIH, National Institute of General Medical Sciences, grant P30 GM124169. Some molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH R01 GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. The graphical abstract was created with BioRender.com. Conceptualization, J.V.R. C.B. D.H. T.L.L. C.W. M. Pravetoni, and M. Pancera; methodology, J.V.R. C.B. D.H. T.L.L. C.W. M. Pravetoni, and M. Pancera; investigation, J.V.R. C.B. D.H. T.L.L. C.W. and A.W.; resources, C.B. D.H. R.J. S.R. and M. Pravetoni; formal analysis, J.V.R. T.L.L. C.W. and P.B.R.; writing – original draft, J.V.R and M. Pancera; writing – review and editing, J.V.R. C.B. D.H. A.T.M. R.K.S. M. Pravetoni, and M. Pancera; supervision, J.V.R. R.K.S. M. Pravetoni, and M. Pancera; funding acquisition, M. Pravetoni and M. Pancera. M. Pravetoni, D.H. and C.B. are inventors of provisional and non-provisional patent applications covering the anti-fentanyl mAbs described herein. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Funding Information:
We are particularly grateful to Julian Simon and Nick Hurlburt for their help in reviewing and preparing this paper and its figures, and to Leo Stamatatos for use of laboratory space and equipment. We are grateful to Mark LeSage for the gift of NIC311 IgG. We thank the J.B. Pendleton Charitable Trust for its generous support of Formulatrix robotic instruments. This work was funded by grants UG3 DA047711 and U01 DA051658 from the National Institutes of Health (NIH) and the National Institute on Drug Abuse (NIDA) (M. Pravetoni and M. Pancera). Some results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source, under US Department of Energy , Office of Biological and Environmental Research contract DE-AC02-06CH11357 . Further work was performed at the Berkeley Center for Structural Biology, which is supported in part by the Howard Hughes Medical Institute . The Advanced Light Source is a Department of Energy Office of Science User Facility under contract no. DE-AC02-05CH11231 . The Pilatus detector on 5.0.1. was funded under NIH grant S10 OD021832 . The ALS-ENABLE beamlines are supported in part by the NIH , National Institute of General Medical Sciences , grant P30 GM124169 . Some molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH R01 GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases . The graphical abstract was created with BioRender.com .

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

  • crystal structure
  • fentanyl
  • ligands
  • mAbs
  • morphine
  • nicotine
  • opioid use disorder
  • oxycodone
  • vaccine

PubMed: MeSH publication types

  • 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.

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