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Characterizing native and hydrocarbon-stapled enfuvirtide conformations with ion mobility mass spectrometry and hydrogen–deuterium exchange

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DOITrouver le DOI : https://doi.org/10.1021/jasms.0c00453
AuteurRechercher : 1Identifiant ORCID : https://orcid.org/0000-0002-7265-9344; Rechercher : ; Rechercher : ; Rechercher : 1
Affiliation
  1. Conseil national de recherches Canada. Centre de recherche en métrologie
FormatTexte, Article
Sujetpeptides and proteins; conformational dynamics; ions; conformation; molecular structure
Résumé
The number of approved peptide therapeutics, as well as those in development, has been increasing in recent years. Frequently, the biological activity of such peptides is elicited through the adoption of secondary structural elements upon interaction with their cellular target. However, many therapeutic peptides are unstructured in solution and accordingly exhibit a poor bioavailability due to rapid proteolysis in vivo. To combat this degradation, numerous naturally occurring peptides with therapeutic properties contain stabilizing features, such as N-to-C cyclization or disulfide bonds. Recently, hydrocarbon stapling via non-native amino acid substitution followed by ring-closing metathesis has been shown to induce a dramatic stabilization of α-helical peptides. Identifying the ideal staple location along the peptide backbone is a critical developmental step, and methods to streamline this optimization are needed. Mass spectrometry-based methods such as ion mobility (IM) and hydrogen–deuterium exchange (HDX) can detect multiple discrete peptide conformations, a significant advantage over bulk spectroscopic techniques. In this study we use IM-MS and HDX-MS to demonstrate that the native 36-residue enfuvirtide peptide is highly dynamic in solution and the conformational ensemble populated by stabilized constructs depends heavily on the staple location. Further, our measurements yielded results that correlate well with the average α-helical content measured by circular dichroism. The MS-based approaches described herein represent sensitive and potentially high-throughput methods for characterizing and identifying optimally stapled peptides.
Date de publication
Maison d’éditionAmerican Chemical Society
American Society for Mass Spectrometry
Dans
  • Journal of the American Society for Mass Spectrometry 32, nº 2 : 753–761.
Langueanglais
Publications évaluées par des pairsOui
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Identificateur de l’enregistremente6ee8286-a125-4f69-92db-44be8b4d037d
Enregistrement créé2021-02-25
Enregistrement modifié2022-03-23

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