A client of Concept Life Sciences had discovered a series of innovative peptides with strong phenotypic potency. However, progress was hindered by a lack of target engagement data, which limited the ability to optimize the peptide series effectively.
Initial in vivo pharmacokinetic (PK) studies on the most promising lead compound revealed parameters that were not suitable for the intended therapeutic application, including a particularly short half-life.
Concept Life Sciences was tasked with improving both the potency and PK profile of the peptides to deliver a compound suitable for in vivo efficacy testing, with the ultimate goal of identifying a viable development candidate.
Concept Life Sciences’ approach
Customized target engagement assays
An SPR target engagement assay was developed to provide both a direct confirmation of target engagement and binding affinities and kinetics. This assay afforded the client valuable insight into the chemical matter’s pharmacological optimization.
Peptide-focused ADME cascade
Peptide discovery requires the use of specific ADME cascades, which are key to the efficient triage of new compounds. It was, therefore, necessary to reshape the project cascade to include key readouts, including plasma stability, solubility, and cellular permeability, as well as in vivo PK profiling in relevant tiers.
An integrated approach to medicinal chemistry
Co-location of chemistry, biology, and DMPK services allows Concept Life Sciences’ scientists to communicate both effectively and efficiently, ensuring leaner optimization campaigns.
Early synthesis route optimization
Seamless integration of Concept Life Sciences’ co-located discovery and process development teams is central to de-risking and accelerating the scale-up process and providing a more rapid proof of concept. This organizational setup is also key to unlocking additional funding tranches at the earliest opportunity.
Concept Life Sciences’ solution
Addressing the lack of target engagement data
The full-length target protein and its two binding domains were prototyped separately, immobilizing each protein individually on CM5 SPR chips. This approach enabled binding measurements for a range of peptide hits, demonstrating specific binding to one of the two domains and highlighting both target engagement and the mechanism of action.
This assay provided both binding affinities and kinetics, offering a range of benefits over the phenotypic assay that had been initially developed for the project. Using this assay, it was possible to rapidly characterize and triage a new compound, improving affinities and potencies more than 5-fold versus the best peptide Leads.
Developing a peptide-specific assay cascade
Concept Life Sciences’ scientists completed the DMPK profiling of cherry-picked Leads in order to define in vitro and in vivo parameters. This process highlighted development challenges and metabolic soft spots both generally inherent to peptides and specific to this project.
A fit-for-purpose DMPK cascade was developed via this profiling, which was then used to identify optimized Leads with in vitro and in vivo half-lives enhanced by more than 50-fold. These Leads provided the required free levels to engage the target in vivo and elicit the desired pharmacology.
This newly developed cascade also provided an efficient means of optimizing the peptide Lead series, focusing the budget on the most promising compounds and saving months of research.
Image Credit: Concept Life Sciences
Peptide lead optimization in medicinal chemistry
Peptides are notoriously difficult to optimize due to their high polarity, low permeability, and poor metabolic stability.
In close collaboration with our biology and DMPK teams, our medicinal chemists developed a critical path for the project and implemented a range of design strategies to address the key liabilities of the lead series. These included strategic truncation of the peptide sequence, incorporation of peptidomimetics, and N- and C-terminal capping.
Within just six months of research, the team successfully tackled a broad set of challenges and identified a peptide suitable for further development.
Peptide synthesis and scale-up readiness
The project rapidly progressed, prompting the need for higher peptide quantities for testing in animal models and other advanced studies.
Concept Life Sciences’ process development team worked alongside the co-located process development team to identify an optimized solution-based synthetic route, facilitating the production of 10 g of high-purity material. The client also used this route to deliver material to support IND enabling studies, opening the door to the GMP production of the API.
Project results
The strategic, integrated approach outlined here resulted in a rapid and efficient optimization process. Key achievements of this project included:
- A x5 increase in affinity as a direct outcome of the medicinal chemistry strategy and tailored SPR assay implemented
- A more than 50-fold improvement in peptide stability, with enhanced mouse and human blood stability, allowing rapid enzymatic degradation challenges to be overcome
- A highly efficient optimization cycle with accelerated project timelines that led to achieving a development candidate in less than 6 months
- Seamless transition to IND-enabling studies, with process optimization enabling the rapid scale-up necessary for regulatory progression
- Compound due to progress into Phase I
Summary
The data-driven peptide optimization strategy described in this case study facilitated the rapid advancement of a peptide, highlighting the value of Concept Life Sciences’ tailored biophysics, ADMET, and medicinal chemistry expertise in the development of peptide drugs.
About Concept Life Sciences
Concept Life Sciences is a leading contract research organisation (CRO) serving the global life sciences industry. For over 25 years, the company, and its heritage companies, have provided consultative and collaborative drug discovery and development services. Our approach, supported by passionate scientists and world-leading capabilities, enables clients to overcome complex scientific challenges across a broad range of therapeutic areas, improving program success rates. The company has successfully helped 29 candidates advance to the clinic.
The company offers sophisticated translational biology services coupled with exceptional end-to-end chemistry capabilities across all modalities, including small molecules, biologics, peptides and cell & gene therapies, with the ability to seamlessly integrate capabilities and provide bespoke solutions to address client needs.
Collectively, the company’s high-quality services and commitment to customer service across the drug development pathway enhance efficiency in drug discovery, helping clients advance their drugs to clinic in as little as 32 months, well ahead of the industry average of 60 months.
Driven by a passion for science, Concept Life Sciences has around 230 employees, with around 70% holding PhDs. The company operates from state-of-the-art UK facilities, headquartered near Manchester, with additional operations in Edinburgh, Dundee, and Sandwich. The headquarters is one of the UK’s largest medicinal chemistry CRO sites with key discovery services all under one roof.
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