An Integrated Approach to Cyclic Peptide Discovery

Flexibility and agility are critical to meeting project demands of drug discovery projects. This program required an exceptionally swift turnaround between purification, biological testing, and ADME profiling to seamlessly feed the design-make-test cycle.

A key challenge was the complexity of the synthetic chemistry, often resulting in low final product yields. Despite this, timely purification and delivery of high-quality peptides were essential for downstream testing and data-driven decision-making.

Our co-location allowed for a fully integrated approach. A close collaboration between chemistry, purification, and biology teams, enabled real-time communication and efficient handover of compounds for testing.

Key strategies included:

• Optimized synthesis workflows – Utilizing automated and manual SPPS strategies to efficiently generate peptide sequences at the required scale.
• Dedicated purification expertise – Ensuring crude peptides (<5% purity) were refined to >95% purity using high-resolution reverse-phase preparative HPLC.
• Efficient compound handover – Streamlining the synthesis-to-testing workflow to ensure purified peptides were ready for biological evaluation within a week.
• Real-time collaboration – Continuous feedback between chemistry, purification, and biology teams to anticipate and resolve challenges quickly.

We implemented a structured workflow to ensure the rapid and efficient synthesis, purification, and handover of high-quality peptides:

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• Tailored solid-phase peptide synthesis (SPPS) techniques – Balancing automation for routine sequences and manual synthesis for complex peptides.
• Advanced purification methodologies – Utilizing state-of-the-art reverse-phase preparative HPLC to refine crude products to high purity.
• Analytical rigor – Deploying UPLC-MS with UV, MS, and ELS detectors to optimize reaction monitoring and purity assessment.
• Integrated biological and ADME testing – Enabling seamless stock solution sharing and immediate profiling of peptides post-purification.

By combining chemistry, purification, and ADME/DMPK capabilities under one roof, we successfully streamlined peptide synthesis and testing:

• Same-week compound profiling – Purified peptides were tested and analyzed within 24 hours of isolation.
• Maximized compound utilization – Despite some peptides yielding less than 0.5 mg, our integrated approach ensured efficient stock sharing across teams.
• Accelerated drug discovery cycles – The rapid turnaround enabled fast decision-making, keeping the project on track.

Through this collaborative and efficient workflow, we demonstrated the power of an integrated approach to peptide drug discovery, ensuring high-quality data generation while maintaining speed and flexibility.