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Chart showing the number of approvals on new drug entities (NDEs) from 2016 to 2023.
Chart showing the number of approvals on new drug entities (NDEs) from 2016 to 2023.
NMR Instruments

Peptides and Oligonucleotides (TIDES)

Small but mighty. Achieve enhanced characterization of complex oligonucleotides and peptides (TIDES) using state-of-the-art technology and methods.

Highlights

Sensitive
Accelerate structure assignments and pinpoint structural changes with new probe and magnet technologies
Selective
Leverage acquisition of select nuclei such as 31P or 19F for even greater selectivity and resolution
Quantitative
Accurately determine absolute content or measure the PS to PO linkage ratio of oligos without reference material

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 entities1-6. Recent FDA and EMA draft guidance documents8-10 demand enhanced characterization of TIDES (including distinguishing stereoisomeric character), which calls for state-of-the-art analytical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.

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.



 

                                     Ascend Evo 1.0 GHz NMR

Applications

Comparison of 1D 1H NMR spectra of exenatide (a GLP-1L antidiabetic drug) using a 5 mm TCI CryoProbe (red) versus a 3 mm MNI CryoProbe (blue) to demonstrate the difference in sensitivity. 
Comparison of 2D 1H-13C HSQC spectra of exenatide (a GLP-1L antidiabetic drug) using a 5 mm TCI CryoProbe (red) versus a 3 mm MNI CryoProbe (blue) to demonstrate the difference in sensitivity.
Improved resolution and selectivity is achieved by 31P NMR using the MNI CryoProbe for easy determination of PS/PO ratio demonstrated on a 16-mer oligonucleotide.
Enhanced characterization of the PS enantiomeric centers of a 16-mer oligonucleotide are facilitated by 2D 1H-31P NMR using the MNI CryoProbe.
Comparison of 2D 1H-13C HSQC spectra at 600 MHz and 1GHz of a 16-mer oligonucleotide highlights the enhanced resolution and sensitivity necessary for heightened characterization.
2D 1H-13C TOCSY spectra at 1GHz of a 16-mer oligonucleotide highlights the enhanced resolution and sensitivity necessary for characterizing the diastereomeric population distribution of PS-modified oligonucleotides.

Characterization of Therapeutic Oligonucleotides by NMR at 1 GHz and 600 MHz

Therapeutic oligonucleotides (ONs) are a new class of molecules that hold great promises to treat pathologies that cannot be cured with classical therapies. Their accurate characterization is critical for both the pharmaceutical industry and regulatory agencies.

Case Studies

Webinars

Discovery of small molecules that target RNA. NMR is the method of choice.
ON DEMAND SESSION – June 18, 2024

Validation and implementation of qNMR as platform methods of oligonucleotides and peptides

The content of e.g peptides or oligonucleotides in a sample (solid or liquid) is of importance in many aspects. For peptides traditional methods like Kjeldahl nitrogen determination, elementary analysis (EA), and amino acid analysis (AAA), requires break down of the protein at harsh conditions to determine the protein content. For oligonucleotides one of the most widely used techniques for quantification is ultraviolet (UV) spectroscopy.
Discovery of small molecules that target RNA. NMR is the method of choice.
ON DEMAND SESSION – November 1, 2023

NMR spectroscopy, just what you need to assure the quality of your TIDES!

The wealth of structural information that accompanies NMR spectroscopy has made it instrumental for traditional small molecules medicinal and analytical chemistry support. Perhaps less well known is its ability to characterise TIDES efficiently and with such a level of detail (atomic resolution). This talk demonstrates its power with examples covering TIDES structure-based drug design,1,2 similarity assessment,3 characterisation,4 secondary and tertiary structure, quantification and phosphorothioate chirality.5,6
Discovery of small molecules that target RNA. NMR is the method of choice.
ON DEMAND SESSION – December 5, 2023

Rational Design of a New Generation of Therapeutic Oligonucleotide Tools

The focus of this webinar will be on the development of new chemical modification approaches to enhance the properties of oligonucleotide drugs. Special attention will be given to cancer and other multi-factorial disorders.
Discovery of small molecules that target RNA. NMR is the method of choice.
ON DEMAND SESSION – March 12, 2024

Oligonucleotide-based Therapeutics: NMR Techniques for Characterization

As the importance and number of Oligonucleotide therapeutics grows, so too does the need for characterization methodologies both during drug development and production.
Discovery of small molecules that target RNA. NMR is the method of choice.
ON DEMAND SESSION – February 8, 2023

Discovery of small molecules that target RNA. NMR is the method of choice.

NMR is the method of choice for fragment-based screening (FBS) of both protein and RNA targets.
covid19.jpg
August 30, 2021

The Role of NMR in the Pandemic

During this one-hour session, we will discuss how NMR is being used to fight COVID-19.

News & Events

Bruker Announces Strategic Minority Investment in NovAliX

NovAliX is a drug discovery focused CRO with award-winning chemistry teams and one of the world’s most comprehensive biophysics platforms. Bruker and NovAliX intend to collaborate on enabling new paradigms in drug discovery, leveraging advanced biophysical methods, and NMR in particular, to structural, binding and functional characterization.
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Collaboration Agreement between the University of Barcelona and Bruker BioSpin for Developing New Applications for the Pharmaceutical Industry at 1 GHz

We are pleased to announce a collaborative agreement with the University of Barcelona to develop and demonstrate new or enhanced applications of NMR at 1 GHz for the pharmaceutical industry, especially in biologics and new drug modalities. The University of Barcelona installed in 2022 the first Avance Evo 1 GHz NMR instrument in Europe and is part of the Spanish Singular Scientific and Technical Large Scale Facilities network. The collaboration includes the synthesis of model therapeutic oligonucleotides by Dr. Terraza’s group at the University of Barcelona. Other therapeutics of interest are monoclonal antibodies, RNA, oligonucleotides, and peptides. This responds to the need of improving product risk assurance and the encouragement by the regulatory authorities to use state-of-the art technology, including NMR.
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Science’s 2023 Breakthrough: GLP-1 Agonists Show Promise Against Obesity-Associated Diseases

Science's 2023 breakthrough goes to Glucagon like peptide-1 (GLP-1) agonists, because of the importance of the research and their impacts across society. These new therapies are reshaping not only how obesity is treated, but how it’s understood—as a chronic illness with roots in biology, not failure of willpower.
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What Do You Think Was the Single Most Consequential Event or Result in Pharma/Biopharma in 2023?

In parallel, we also highlighted in the new Pharma’s Almanac roundtable the approval of glucagon-like peptides for the treatment of obesity as a major consequential event in 2023. The size and structural properties of GLP-1 and GIP agonists make them ideally suited to be studied by NMR, benefiting from the quantitative nature and wealth of structural information that accompanies the technique.
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