By Bachem AG
Bachem glycosylated peptides
Bachem offers a new service that permits the synthesis of peptides and proteins with pre-attached sugars. Through the chemical glycosylation technology the pharmacokinetic profile of drugs can be improved.
The partnership between Bachem and GlyTech is focused on the chemical development and manufacturing of glycosylated peptides.
Chemical glycosylation of peptides markedly improves drug properties such as half-life, binding affinity and selectivity. Furthermore, chemically synthesized proteins are more homogeneous than recombinant products.
Bachem has the proven expertise to scale up and manufacture kilogram scale peptides, while GlyTech is capable of producing glycans in kg amounts, using proprietary technology.
More than 50 glycans are available from a developed library.
Glycopeptide applications
Glycosylation of peptide drugs provides a powerful way to optimize lead drug candidates. Selective, site-specific glycosylation leads to a homogeneous product with potential for more defined bioactivity compared to heterogeneous products.
Glycosylation of peptide drugs can also result in:
- Increased half-life, providing extended dosing duration
- Enhanced solubility, enabling improved formulation properties
- Better tolerance of resulting drugs
- Improved response to therapy
Chemical glycosylation advantages
Traditional recombinant production of glycopeptides faces the problems of heterogeneity, elaborate and costly purification processes, requiring removal of biological contaminants such as cellular debris or viruses.
In contrast, selective, site-specific chemical glycosylation leads to a more homogeneous product with potential for more defined bioactivity compared to heterogeneous products. The chemical synthesis produces well-defined glycopeptides and allows developer to:
- Attach any glycan at the desired position
- pecify the number of attached glycans
- Control the glycan structure
Selective glycosylation can improve the physicochemical properties of peptides in respect of:
- Binding (Kd)
- Half-life
- Stability
- Homogeneity
These enhanced physicochemical properties can positively improve the pharmacokinetic profile of a lead candidate drug, producing, for example, improved bioactivity, greater receptor selectivity and longer half-life.
Most chemically synthesized peptide drugs can be easily adapted to glycosylation at competitive production costs.
Glycosylation process
Bachem has synthesized numerous glycopeptides, including glyco-somatostatin analogues and glyco-GLP-I analogues. Glycosylation projects typically follow a five-phase process:
LEAD OPTIMIZATION
- Compound properties not satisfactory
- Definition of current compound properties
- Identification of desired compound properties
DESIGN PHASE
- Scientific dialogue and collaboration between partner and Bachem/GlyTech
- Design a number of compounds expected to meet desired properties
SYNTHESIS & SUPPLY
- Synthesis of compounds at milligram or gram scale for research purpose (non-GMP)
- The compounds get supplied with the agreed sequence, structure and quantity
TEST PHASE
- Positive results may lead to a License Agreement
- Results may lead to another iteration of Design Phase for further improvement of the lead compound
SCALE- UP
- Scale-up and analytical development at Bachem
- Manufacturing according to cGMP
Glycosylation proof of concept: Interferon β-1a
Bachem Holding AG and GlyTech, Inc. have proved the chemical synthesis route to glycosylation with their pioneering work on Interferon β-1a, for which they were jointly named finalists for the Innovation Prize at the 2013 CPhI Awards.
Interferon β-1a is a glycosylated 166 amino acid protein and an approved drug substance to treat multiple sclerosis with a world market of more than $ 4 billion. There are currently three recombinant products on the market, which are mixtures of at least 10 glycoforms.
Bachem and GlyTech succeeded in chemically synthesizing Interferon β-1a. Compared to the recombinant compounds, chemically glycosylated Interferon exhibited:
- Lower heterogeneity (no glycoforms)
- Extended half-life
- Improved in vitro binding
- Enhanced in vivo efficacy
New generation synthesized glycopeptides
The Interferon synthetic process was optimized for cost-effective industrial-scale manufacturing by Bachem, paving the way for a new generation of chemically synthesized glycopeptides with important positive implications for the industry:
- Widening the scope of peptide optimization beyond simple amino acid sequencing
- Improving approved drugs that fall short
- Aiding development of challenging new drugs
- Creating increased intellectual property value
The Bachem/GlyTech technology has been used in multiple other projects, such as to manufacture glycosylated somatostatin analogues and glycosylated GLP-1. In all cases, drug improvements were achieved.
Bachem CMO, Dr. José de Chastonay, defines the overall vision when he says:
“The selective chemical glycosylation at large scale has potential to be applied to a variety of peptides, where we can pioneer the concept of improving current and future drugs via chemical glycosylation.”
Glycopeptide APIs via chemical synthesis
Selective glycosylation can improve the physicochemical properties of peptides, due to the following factors:
- Chemical synthesis can generate well-defined glycosylated structures, allowing optimal choice of the glycosyl moiety and its position
- Both moieties; chemical structure and position of glycosyl; can markedly improve the biological activity of a peptide
- A comprehensive library of glycans, containing human glycoproteins linked to asparagine, has been created
Glycan Library
One powerful way to enable optimization of lead drug candidates is to generate a range of pre-glycosylated analogs (glycans) in a “library” approach. This delivers the following benefits:
- For each lead peptide chosen for glycosylation, a human type glycoprotein is available from the library
- Optimized glycopeptide designs can be selected by a joint project team of client together with Bachem and GlyTech, to benefit from respective expertise
- Synthetically glycosylated peptides can be produced in small (mg-g) scale by GlyTech
- The glycosylated peptides can be screened by the client in order to find a glycopeptide with improved pharmacological properties
- The selected glycopeptide with enhanced properties can then be scaled- up and manufactured by Bachem in the required quantities
Discounts
Visit the Bachem online catalog to see the full collection of peptides, building blocks and biochemicals, all available for fast delivery.
Pharmaceutical Networking users qualify for an exclusive 10% discount on the online SPPS products featured here.
Just enter promotional code PN10 when placing your order to receive these special discounted prices.
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