Peptides and Oligonucleotides (TIDES)

Peptides and oligonucleotides (TIDES) are important and potent therapeutic modalities in targeting many diseases: diabetes, cancer, osteoporosis, cardiovascular diseases, genetic disorders, and other rare diseases to name a few. Nuclear magnetic resonance (NMR) spectroscopy is the best-suited, high-resolution technique for structure characterization of these modalities, including higher order structure (HOS), chiral identification, and comparability and similarity assessments. The inherent benefits (specificity, safety, efficacy, druggable indications, and low cost) of TIDES has led to a growing interest in R&D in the biopharmaceutical industry: from 2016 and 2023 TIDES make up about 13% of all FDA-approved new drug entities^1-6. Recent FDA and EMA draft guidance documents^8-10 demand enhanced characterization of TIDES (including distinguishing stereoisomeric character), which calls for state-of-the-art analytical techniques and NMR is recommended to meet these needs.

NMR is widely viewed as the “gold standard” for chemical structure characterization of various and advances in sensitivity, resolution, and data processing enables detailed characterization to support discovery, development, and manufacturing of TIDES. The introduction of the Ascend Evo instruments improves the accessibility of magnets at higher field strengths, especially the 1 GHz instrument, to be employed for TIDES characterization because of the reduction in footprint and maintenance of cryogenic fluids. The gain in resolution at higher field strengths accelerates the assignment process of peptides and facilitates the characterization of the enantiomeric complexity of oligos, both of which are important in therapeutic development. Additionally, the development in probe technology improves the mass-sensitivity at common field strengths (500 and 600 MHz) and allows for direct detection of nuclei unique to oligos. The 3 mm Multi-Nuclear Inverse (MNI) CryoProbe™ enhances sensitivity relative to other similar CryoProbes (e.g., 5 mm TCI CryoProbe) to further accelerate the assignment of peptides and has a channel tunable to ¹⁹F and ³¹P for enhanced characterization of oligos. Despite the chemical and dynamic complexity of peptides and oligos, these improvements to NMR technology enable scientists to rise to the challenge of TIDES characterization to ensure patient safety.

<sup>1. O.A. Musaimi, D.A. Shaer, B.G. De la Torre, and F. Albericio. Pharmaceutical. 2018; 11. 42-51.
2. D.A. Shaer, O.A. Musaimi, F. Albericio and B.G. De la Torre. Pharmaceutical. 2019; 12. 52-57.
3. D.A. Shaer, O.A. Musaimi, F. Albericio and B.G. De la Torre. Pharmaceutical. 2020; 13. 40-54.
4. D.A. Shaer, O.A. Musaimi, F. Albericio and B.G. De la Torre. Pharmaceutical. 2021; 14. 145-158.
5. D.A. Shaer, O.A. Musaimi, F. Albericio and B.G. De la Torre. Pharmaceutical. 2022; 15. 222-138.
6. O.A. Musaimi, D.A. Shaer, F. Albericio and B.G. De la Torre. Pharmaceutical. 2023; 16. 336-345.
7. D.A. Shaer, O.A. Musaimi, F. Albericio and B.G. De la Torre. Pharmaceutical. 2024; 17. 243-155.
8. US Department of Health and Human Services, FDA. ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin. May 2021. https://www.fda.gov/media/107622/download. Accessed 27-Apr-2024.
9. US Department of Health and Human Services, FDA. Draft Guidance on Givosiran Sodium. May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_212194.pdf. Accessed 27-Apr-2024.
10. European Medicines Agency. Guideline on the Development and Manufacture of Synthetic Peptides. Oct 2023. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-development-and-manufacture-synthetic-peptides_en.pdf. Accessed 27-Apr-24.</sup>