PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective
Version 1
: Received: 28 March 2024 / Approved: 28 March 2024 / Online: 28 March 2024 (13:39:38 CET)
How to cite:
Li, W. Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective. Preprints2024, 2024031756. https://doi.org/10.20944/preprints202403.1756.v1
Li, W. Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective. Preprints 2024, 2024031756. https://doi.org/10.20944/preprints202403.1756.v1
Li, W. Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective. Preprints2024, 2024031756. https://doi.org/10.20944/preprints202403.1756.v1
APA Style
Li, W. (2024). Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective. Preprints. https://doi.org/10.20944/preprints202403.1756.v1
Chicago/Turabian Style
Li, W. 2024 "Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective" Preprints. https://doi.org/10.20944/preprints202403.1756.v1
Abstract
As a key mediator of chronic pain, neurotrophin nerve growth factor (NGF) binds to two neurotrophin receptors: p75 neurotrophin receptor (p75NTR) and tyrosine kinase receptor A (TrkA). The formation of the p75NTR-NGF-TrkA complex is implicated in the potentiation of chronic pain signals, making it an attractive target for therapeutic explorations. NGF analogues and monoclonal antibodies (mAbs) targeting NGF represent two distinct approaches in modulating the intricate signaling pathways involved in pain transduction mediated by the p75NTR-NGF-TrkA complex. While NGF analogues offer the advantage of tailored design to fine-tune neurotrophic responses, monoclonal antibodies provide a more systemic and comprehensive blockade of NGF, inhibiting its interactions with both p75NTR and TrkA receptors. However, the use of mAbs may pose challenges related to potential side effects and interference with the physiological functions of NGF. As a result, balancing the benefits and drawbacks of the two approaches is critical for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain. In this study, therefore, a novel structural and biophysical approach was employed for the design of NGF analogues to suppress p75NTR-NGF-TrkA-related chronic pain signaling. Employing high-throughput structural modeling and biophysics-based intermolecular binding affinity calculations, this article for the first time puts forward a set of NGF analogues, including in particular NGF analogues with four site-specific mutations, for whose dimerizations the K d at 37 ◦C were reduced by three orders of magnitude (from 10-9 M to 10-6 M) compared to the K d at 37 ◦C for the dimerization of native NGFs. Overall, the integration of structural and biophysical perspectives enhances our understanding of the rational design of NGF analogues as promising candidates for the development of NGF-targeted analgesic therapies, which balances the benefits and drawbacks of anti-NGF antibodies and NGF analogues for advancing therapeutic strategies towards the alleviation of p75NTR-NGF-TrkA-mediated pain.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
