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Glepaglutide, A Long-Acting GLP-2 Analog in Development for the Treatment of Short Bowel Syndrome
Zealand Pharma A/S
Discovery and Development of a New Class of Macrocyclic Peptide Antibiotics
We have developed a maskless photolithography peptide synthesis and screening platform that has been applied both for lead discovery and optimization. Our chemical catalog of over 350 amino acid building blocks combined with rapid library design and robust workflows, allows synthesis of over 18 million unique linear or cyclic peptides in less than 48 hrs on a single glass slide. The process is scalable and large libraries of millions of peptides can be synthesized on demand. We have made incremental upgrades and exploring end-point detection, real-time kinetic interaction, and cell-based phenotypic assays. Here, we will describe the core technology and its application to rapidly and systematically evolve high-affinity, high-specificity binding peptides to protein targets in a reproducible and digitally controlled process. We will demonstrate some case-examples, and recent process upgrades that enable real-time kinetic analysis for thousands of peptide-protein interactions in parallel.
The peptide discovery platform is based on an mRNA display technique that is able to identify a variety of high affinity binding peptides. They have typically macrocyclic scaffold and contain natural and non-natural amino acids. These peptides can support drug discovery projects in different manners and some examples will be shown. Further method developments and innovations to generate more impact of the platform will be also presented.
Aggregation of the alpha-Synuclein (aS) protein inside dopamine producing cells leads to PD by forming toxic Lewy bodies that interfere with normal brain function. We are utilising vast peptide libraries to identify those that both bind but most importantly are able to effectively block aS associated toxicity. Novelty lies in the fact that peptide selection is undertaken entirely inside living cells, with no assumptions made regarding mechanism of binding. Further novelty lies in the 45-54 region of aS which serves as a template for our library designs. This region is frequently mutated in early onset PD and is key to the pathogenic structure recently identified from CryoEM studies. Intracellular library screening and selection removes promiscuous peptides that bind to other proteins, as well as those that are unstable, insoluble, and degraded by enzymes. The most promising compounds have been characterised using a range of biophysical, structural, and cell-based experiments to i) increase understanding of how aggregation and toxicity are coupled, and ii) generate molecules for future use in PD diagnostics and prevention.
In parallel to activity optimisation at the target receptor(s), we consider physical & chemical peptide properties as primary optimisation parameter. For this purpose, orthogonal experimental methods and different in silico approaches are continuously implemented and applied in an iterative manner for the optimisation of functional, physical & chemical peptide properties, considering requirements of the final drug product.
An overview of progression of glepaglutide from lead optimisation to Phase III clinical studies.
This presentation focuses on the discovery of the outer-membrane targeting antibiotic (OMPTA) class applying PEM technology . OMPTAs target specifically Gram-negative bacteria by binding to lipopolysaccharide and outer-membrane proteins. Murepavadin (POL7080) is in phase III and the first member of this class . The discovery and development up to preclinical stage of a novel class of OMPTA with medium-spectrum activity against all Gram-negative priority 1/ESKAPE pathogens overcoming also colistin resistant strains will be described.
Panelists made up of a selection of speakers from the event
Workshop organized by Zeochem AG. This evening workshop will focus on novel developments in the cost-efficient production of peptides. Through a series of presentations, the following areas will be addressed:
• Enzymatic peptide synthesis
• Silica based purification
Working Title: “When Upstream meets Downstream processing: It takes two to have an efficient manufacturing process”
Dr. Ralf Eisenhuth, Teamleader API CMC Development, Bachem AG, Switzerland
Chemo-enzymatic synthesis (CEPS) of Liraglutide and Semaglutide
The linear SPPS manufacture of generic forms of acylated GLP-1 analogs such as liraglutide and semaglutide is especially demanding because the innovators use recombinant expression, which inherently generates challenging impurity profiles that in turn lead to low overall yields. In our presentation, we report efficient chemo-enzymatic peptide synthesis (CEPS) manufacturing processes for the block-buster incretin peptides such as exenatide, liraglutide and semaglutide. In general, the overall yield obtained from the production of incretin peptides using CEPS is more than doubled as compared to linear SPPS.
Dr. Timo Nuijens, CSO, EnzyPep BV, Netherlands
Cost Efficient Peptide & Oligonucleotide Purification via ZEOsphere DRP Mixed-Mode Chromatography
The workshop will show the beneficial use of ZEOsphere DRP Mixed-Mode stationary phases in the repulsive-attractive mode compared to RP or IEX stationary phases on crude peptides and oligonucleotides. ZEOsphere DRP orthogonal interaction is due to a better selectivity not only able to increase purity, recovery and loading, but also to decrease the organic solvent usage. Real Peptide and Oligonucleotide crude separation will be discussed.
Mr. Jürgen Machielse, Business Development Director, Zeochem AG, Switzerland
The Role of Big Data and Digitalization Technologies for Drug Manufacturing
Following the examples of successful process digitalization and automation in the ‘older industries’ such as automotive and finance, several trends could be observed in the biopharmaceutical industry. In order to eventually fulfill the standards and goals of the industry 4.0 era, these methodologies and technologies must be further developed and extensively utilized in the (bio)pharmaceutical process industry.
Throughout the past years, we elaborated several digital solutions based on advanced engineering statistics, machine learning and deterministic approaches for the analysis, modeling and interpretation of biomanufacturing processes. Furthermore, we integrated them into the process development workflow in several collaboration projects with the (bio)pharmaceutical industry. This presentation will outline key technology and business drivers to master the digital transformation challenge in bio(pharma). It will show the possibilities to accelerate development as well as to reduce risks and resources in scale-up and production based on several industrial case studies.
Dr. Alessandro Butté, CEO DataHow AG, Switzerland