A C-terminal cysteine residue is required for peptide-based inhibition of the NGF/TrkA interaction at nM concentrations:implications for peptide-based analgesics

Poole, Andrew, Frigotto, Laura, Smith, Matthew E., Baar, Claudia, Ivanova-Berndt, Gabriela, Jaulent, Agnes, Stace, Catherine, Ullman, Christopher G. and Hine, Anna V. (2019). A C-terminal cysteine residue is required for peptide-based inhibition of the NGF/TrkA interaction at nM concentrations:implications for peptide-based analgesics. Scientific Reports, 9 (1),

Abstract

Inhibition of the NGF/TrkA interaction presents an interesting alternative to the use of non-steroidal anti-inflammatories and/or opioids for the control of inflammatory, chronic and neuropathic pain. Most prominent of the current approaches to this therapy is the antibody Tanezumab, which is a late-stage development humanized monoclonal antibody that targets NGF. We sought to determine whether peptides might similarly inhibit the NGF/TrkA interaction and so serve as future therapeutic leads. Starting from two peptides that inhibit the NGF/TrkA interaction, we sought to eliminate a cysteine residue close to the C-terminal of both sequences, by an approach of mutagenic analysis and saturation mutagenesis of mutable residues. Elimination of cysteine from a therapeutic lead is desirable to circumvent manufacturing difficulties resulting from oxidation. Our analyses determined that the cysteine residue is not required for NGF binding, but is essential for inhibition of the NGF/TrkA interaction at pharmacologically relevant peptide concentrations. We conclude that a cysteine residue is required within potential peptide-based therapeutic leads and hypothesise that these peptides likely act as dimers, mirroring the dimeric structure of the TrkA receptor.

Publication DOI: https://doi.org/10.1038/s41598-018-37585-5
Dataset DOI: https://doi.org/10.17036/researchdata.aston.ac.uk.00000375
Divisions: Life & Health Sciences
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: This work was funded by BBSRC Grant BB/I016481/1 to A.V.H.
Uncontrolled Keywords: General
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2019-01-30
Authors: Poole, Andrew
Frigotto, Laura
Smith, Matthew E.
Baar, Claudia
Ivanova-Berndt, Gabriela
Jaulent, Agnes
Stace, Catherine
Ullman, Christopher G.
Hine, Anna V. ( 0000-0003-4065-831X)

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