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Review ArticleReview Article

Mass Spectrometry Approaches Empowering Neuropeptide Discovery and Therapeutics

Krishna D. B. Anapindi, Elena V. Romanova, James W. Checco and Jonathan V. Sweedler
Vivian Hook, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 662-679; DOI: https://doi.org/10.1124/pharmrev.121.000423
Krishna D. B. Anapindi
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.)
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Elena V. Romanova
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.)
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James W. Checco
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.)
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Jonathan V. Sweedler
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.)
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Vivian Hook
Roles: ASSOCIATE EDITOR
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Abstract

The discovery of insulin in the early 1900s ushered in the era of research related to peptides acting as hormones and neuromodulators, among other regulatory roles. These essential gene products are found in all organisms, from the most primitive to the most evolved, and carry important biologic information that coordinates complex physiology and behavior; their misregulation has been implicated in a variety of diseases. The evolutionary origins of at least 30 neuropeptide signaling systems have been traced to the common ancestor of protostomes and deuterostomes. With the use of relevant animal models and modern technologies, we can gain mechanistic insight into orthologous and paralogous endogenous peptides and translate that knowledge into medically relevant insights and new treatments. Groundbreaking advances in medicine and basic science influence how signaling peptides are defined today. The precise mechanistic pathways for over 100 endogenous peptides in mammals are now known and have laid the foundation for multiple drug development pipelines. Peptide biologics have become valuable drugs due to their unique specificity and biologic activity, lack of toxic metabolites, and minimal undesirable interactions. This review outlines modern technologies that enable neuropeptide discovery and characterization, and highlights lessons from nature made possible by neuropeptide research in relevant animal models that is being adopted by the pharmaceutical industry. We conclude with a brief overview of approaches/strategies for effective development of peptides as drugs.

Significance Statement Neuropeptides, an important class of cell-cell signaling molecules, are involved in maintaining a range of physiological functions. Since the discovery of insulin’s activity, over 100 bioactive peptides and peptide analogs have been used as therapeutics. Because these are complex molecules not easily predicted from a genome and their activity can change with subtle chemical modifications, mass spectrometry (MS) has significantly empowered peptide discovery and characterization. This review highlights contributions of MS-based research towards the development of therapeutic peptides.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant P30-DA018310] to J.V.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/pharmrev.121.000423.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 74 (3)
Pharmacological Reviews
Vol. 74, Issue 3
1 Jul 2022
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Review ArticleReview Article

Mass Spectrometry for Neuropeptide Discovery

Krishna D. B. Anapindi, Elena V. Romanova, James W. Checco and Jonathan V. Sweedler
Pharmacological Reviews July 1, 2022, 74 (3) 662-679; DOI: https://doi.org/10.1124/pharmrev.121.000423

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Review ArticleReview Article

Mass Spectrometry for Neuropeptide Discovery

Krishna D. B. Anapindi, Elena V. Romanova, James W. Checco and Jonathan V. Sweedler
Pharmacological Reviews July 1, 2022, 74 (3) 662-679; DOI: https://doi.org/10.1124/pharmrev.121.000423
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction: A Century of Neuropeptide/Hormone Discovery: Where Are We and Where Are We Going?
    • II. What Are Neuropeptides and Peptide Hormones?
    • III. Methods of Neuropeptide Discovery and Characterization
    • IV. From Discovery to Function
    • V. Unusual Routes to Peptide Formation and Function
    • VI. The Rise of Biologics: Therapeutic Peptides
    • VII. Conclusions
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