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Main Conference Day 3 - Europe/Amsterdam
- Hannah Bolt, PhD, MBA - Head of Peptide Discovery, AstraZeneca
Recent clinical successes have established targeted covalent inhibitors as a viable strategy in drug discovery, demonstrating their ability to target the so-called ‘undruggable’ proteome where conventional non-covalent molecules often fail. However, the development of covalent ligands to new targets remains a significant challenge, primarily due to the lack of large, diverse, and ready-to-use covalent libraries, impeding the development of novel lead compounds. We addressed this bottleneck by developing a new method for high-throughput solid-phase synthesis of short peptidic compounds that all carry a covalent warhead. Towards this end, we established synthesis procedures compatible with the introduction of reactive electrophiles such as acrylamides, chloroacetamides, sulfonyl fluorides. The peptides are produced in 384-well plates and are released at high purity that omits throughput-limiting purification. Using a combination of non-natural amino acids and non-amino acid building blocks, we synthesized a diverse library of 85,000 sub-kDa peptidic covalent compounds. The library and screening approach was validated in high-throughput screens with the model target thrombin that identified several potent covalent inhibitors. Recently, we applied the strategy to the challenging protein-protein interaction (PPI) targets Keap1-NRF2 and -catenin-TCF that identified potent and selective covalent inhibitors based on the sulfonyl fluoride warhead.
- Gregoire Menoud - Senior PhD student, EPFL
Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) has emerged as a robust and highly efficient technology for peptide manufacturing. By leveraging automated side-cut recycling, MCSGP significantly minimizes the analytical workload and reduces process turnaround time. In this peptide purification example, development efforts prioritized optimizing process efficiency while ensuring operational robustness and seamless scale-up. To validate the robustness, an extensive multivariate characterization strategy was employed, correlating Critical Process Parameters (CPPs) with Critical Quality Attributes (CQAs) via the establishment of Proven Acceptable Ranges (PARs). Systematic analysis of both univariate process variations and complex multiparameter interactions facilitated the definition of Acceptable Ranges (ARs), thereby ensuring robust, reproducible, and high-purity yields at commercial manufacturing scale.
- Martina Niess - Scientist, F. Hoffmann-La Roche Ltd
This presentation explores scalable NMR approaches for peptide characterization, illustrated through case studies spanning short model peptides, long sequences, and an oncology‑relevant therapeutic candidate. We discuss practical strategies to handle sequence length, chemical diversity, and experimental complexity, highlighting how standardized, automation‑ready workflows improve robustness, reproducibility, and throughput in peptide‑focused drug discovery from early research to late‑stage development.
- Shubhadra Pillay, PhD - Solutions Product Manager, Bruker BioSpin
Ensuring the therapeutic performance of phosphorothioate (PS)-modified oligonucleotides requires robust analytical and manufacturing approaches. The PS substitution, used to impart nuclease resistance and improve efficacy, generates a chiral phosphorus centre at each linkage and introduces added complexity to both analysis and control strategy, since clinical material is typically administered as a mixture of P-diastereomers. Because individual diastereomers may differ in pharmacology and biological activity, it is essential to maintain a consistent diastereomeric distribution across drug substance batches to underpin reproducible efficacy. Although maintaining a stable diastereomeric profile is often achieved by holding the coupling activator constant during solid-phase oligonucleotide synthesis (SPOS), it has been proposed that chromatographic purification of single-stranded siRNA can partially resolve diastereomers and risk changing the diastereomeric ratio. From a regulatory perspective, any process change requires an assessment and justification of comparability with respect to the diastereomeric profile. While developing liquid chromatography methods to resolve and quantify diastereomers, we observed that separation is highly sequence dependent, especially influenced by the tendency of single strands to adopt higher-order structures. At AstraZeneca, we demonstrated that substantial diastereomer resolution can occur during strong anion exchange (SAX) purification under specific conditions, creating a potential for altering diastereomer ratios. Our characterisation work connected features of oligonucleotide structure with an elevated risk of diastereomer separation during purification, and thus with a risk of changing the diastereomer distribution. Building on these findings, we outline key considerations for designing a robust, scalable manufacturing process for oligonucleotides and propose mitigations to minimise diastereomeric changes during purification, thereby supporting seamless clinical development without batch-to-batch changes in pharmacological properties. This study illustrates practical analytical and process approaches that enable sustainable scale-up of oligonucleotide therapeutics and streamline regulatory acceptance, ensuring consistent pharmacological behaviour throughout development and commercialisation.
- Joanna Hemming Taylor, PhD - Associate Principal Scientist, AstraZeneca
Priavoid develops disease-modifying therapeutics for neurodegenerative diseases. Its all-D-peptide platform targets pathogenic protein aggregation by stabilizing monomeric proteins and detangling aggregates. Building on clinical-stage PRI-002 for Alzheimer’s disease, the platform has identified Parkinson’s disease candidates that reduce α- synuclein pathology and show brain penetration after oral administration in mice.
- Mathias Wendt, PhD - Senior Peptide Chemist, Priavoid GmbH