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Aggregation Behavior of Structurally Similar Therapeutic Peptides Investigated by 1H NMR and All-Atom Molecular Dynamics Simulations

Hjalte, Johanna LU ; Hossain, Shakhawath ; Hugerth, Andreas ; Sjögren, Helen LU ; Wahlgren, Marie LU orcid ; Larsson, Per and Lundberg, Dan LU (2022) In Molecular Pharmaceutics 19(3). p.904-917
Abstract

Understanding of peptide aggregation propensity is an important aspect in pharmaceutical development of peptide drugs. In this work, methodologies based on all-atom molecular dynamics (AA-MD) simulations and 1H NMR (in neat H2O) were evaluated as tools for identification and investigation of peptide aggregation. A series of structurally similar, pharmaceutically relevant peptides with known differences in aggregation behavior (D-Phe6-GnRH, ozarelix, cetrorelix, and degarelix) were investigated. The 1H NMR methodology was used to systematically investigate variations in aggregation with peptide concentration and time. Results show that 1H NMR can be used to detect the presence of... (More)

Understanding of peptide aggregation propensity is an important aspect in pharmaceutical development of peptide drugs. In this work, methodologies based on all-atom molecular dynamics (AA-MD) simulations and 1H NMR (in neat H2O) were evaluated as tools for identification and investigation of peptide aggregation. A series of structurally similar, pharmaceutically relevant peptides with known differences in aggregation behavior (D-Phe6-GnRH, ozarelix, cetrorelix, and degarelix) were investigated. The 1H NMR methodology was used to systematically investigate variations in aggregation with peptide concentration and time. Results show that 1H NMR can be used to detect the presence of coexisting classes of aggregates and the inclusion or exclusion of counterions in peptide aggregates. Interestingly, results suggest that the acetate counterions are included in aggregates of ozarelix and cetrorelix but not in aggregates of degarelix. The peptides investigated in AA-MD simulations (D-Phe6-GnRH, ozarelix, and cetrorelix) showed the same rank order of aggregation propensity as in the NMR experiments. The AA-MD simulations also provided molecular-level insights into aggregation dynamics, aggregation pathways, and the influence of different structural elements on peptide aggregation propensity and intermolecular interactions within the aggregates. Taken together, the findings from this study illustrate that 1H NMR and AA-MD simulations can be useful, complementary tools in early evaluation of aggregation propensity and formulation development for peptide drugs.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
H NMR spectroscopy, AA-MD simulations, aggregation, evaluation of developability, therapeutic peptides
in
Molecular Pharmaceutics
volume
19
issue
3
pages
14 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:35104408
  • scopus:85124274359
ISSN
1543-8384
DOI
10.1021/acs.molpharmaceut.1c00883
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022 American Chemical Society. All rights reserved.
id
14c0c69a-a27e-433d-ba7b-0993161b6e81
date added to LUP
2022-08-25 05:58:35
date last changed
2025-03-19 04:15:13
@article{14c0c69a-a27e-433d-ba7b-0993161b6e81,
  abstract     = {{<p>Understanding of peptide aggregation propensity is an important aspect in pharmaceutical development of peptide drugs. In this work, methodologies based on all-atom molecular dynamics (AA-MD) simulations and <sup>1</sup>H NMR (in neat H<sub>2</sub>O) were evaluated as tools for identification and investigation of peptide aggregation. A series of structurally similar, pharmaceutically relevant peptides with known differences in aggregation behavior (D-Phe<sup>6</sup>-GnRH, ozarelix, cetrorelix, and degarelix) were investigated. The <sup>1</sup>H NMR methodology was used to systematically investigate variations in aggregation with peptide concentration and time. Results show that <sup>1</sup>H NMR can be used to detect the presence of coexisting classes of aggregates and the inclusion or exclusion of counterions in peptide aggregates. Interestingly, results suggest that the acetate counterions are included in aggregates of ozarelix and cetrorelix but not in aggregates of degarelix. The peptides investigated in AA-MD simulations (D-Phe<sup>6</sup>-GnRH, ozarelix, and cetrorelix) showed the same rank order of aggregation propensity as in the NMR experiments. The AA-MD simulations also provided molecular-level insights into aggregation dynamics, aggregation pathways, and the influence of different structural elements on peptide aggregation propensity and intermolecular interactions within the aggregates. Taken together, the findings from this study illustrate that <sup>1</sup>H NMR and AA-MD simulations can be useful, complementary tools in early evaluation of aggregation propensity and formulation development for peptide drugs.</p>}},
  author       = {{Hjalte, Johanna and Hossain, Shakhawath and Hugerth, Andreas and Sjögren, Helen and Wahlgren, Marie and Larsson, Per and Lundberg, Dan}},
  issn         = {{1543-8384}},
  keywords     = {{H NMR spectroscopy; AA-MD simulations; aggregation; evaluation of developability; therapeutic peptides}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{904--917}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Molecular Pharmaceutics}},
  title        = {{Aggregation Behavior of Structurally Similar Therapeutic Peptides Investigated by <sup>1</sup>H NMR and All-Atom Molecular Dynamics Simulations}},
  url          = {{http://dx.doi.org/10.1021/acs.molpharmaceut.1c00883}},
  doi          = {{10.1021/acs.molpharmaceut.1c00883}},
  volume       = {{19}},
  year         = {{2022}},
}