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Jul 1, 2009 (Vol. 29, No. 13)

Competition Mounting in Peptide Market

Renewed Interest in Peptides from Pharmaceutical Firms Heats Up Sector

  • Improvements

    Other recent advances in peptide synthesis that Dr. Ede feels have contributed to the quality, efficiency, and cost-effectiveness of peptide synthesis are improvements in automated peptide synthesizers, such as Protein Technologies’ line of instruments that includes the Symphony®, Sonata®, Prelude™, and Tribute™.

    “What they have achieved in the last two years—with the development of fast synthesis protocols using HCTU highly activated coupling agents—has helped us enormously,” he says. Dr. Ede also credits the development of microwave-synthesis technology, pioneered by CEM with its Liberty™ automated synthesizer, as having “a profound effect on the ability to synthesize hydrophobic peptides.”

    Protein Technologies recently introduced the Sonata XT peptide synthesizer, doubling the scale of the original Sonata instrument, with a capacity for 400 g of resin and 0.5 to 200 mmol scale synthesis.

    The Sonata XT is GMP compliant, compatible with batch or continuous flow syntheses, offers amino acid delivery options for either in situ activation or preactivation (to minimize unwanted side reactions), and features dual waste streams for reduced disposal costs.

    The new instrument was developed in response to customer demand for increased capacity. As products move through the pipeline and peptide quantities increase, companies want to be able to produce a GMP peptide in a single, larger batch rather than in two or more batches, thereby simplifying traceability and accountability and eliminating the need to duplicate QA/QC and validation protocols, according to Mahendra Menakuru, COO.

    He highlights several key features of the company’s automated synthesizers, primarily the core fluidics technology that minimizes moving parts and is based on a soft-seat membrane valve design; the instruments’ minimal down-time for cleaning and other internal machine processing enabling fast cycle times; and the use of HCTU, a potent coupling reagent that accelerates Fmoc synthesis.

    Also new on the market from Protein Technologies is the IntelliSynth UV-monitoring and feedback control attachment for the Tribute two-channel peptide synthesizer. The system “takes the mystery out of the deprotection reaction,” says Menakuru. It monitors the efficiency of Fmoc removal in real-time by measuring the concentration of dibenzofulvene-piperidine adduct formed. Users can select from two feedback control options that automatically modify deprotection and/or coupling cycles based on the reaction data.

    Despite the increasing strength of the dollar in overseas markets, Menakuru has not seen a decline in business from Europe or Asia. Furthermore, he reports early signs of a reversal in last year’s decline in grant-funded projects, with a substantial rise in inquiries from academia in the early part of 2009 that he attributes to anticipation of NIH stimulus dollars making their way down to funded laboratories.

    Recognizing increasing market demand for an expanded range of peptide substrates for long-wavelength fluorescence resonance energy transfer assays, AnaSpec developed a series of fluorogenic FRET pairs for evaluating protease inhibitors in drug discovery. The assays are commonly used for studying protease activity and screening for protease inhibitors. The company’s FRET peptides incorporate its QXL™ quenchers, which are optimized to pair with AnaSpec’s HiLyte Fluor™ dyes as well as commercial fluorescent dyes.

    The long absorption wavelengths of AnaSpec’s FRET pairs, such as carboxyfluorescein/QXL 520, “eliminate a lot of the autofluorescence” that contributes to background noise and compromises assay sensitivity, according to Cecilia Po, technical support specialist. The company’s most recent product introduction, early this year, featured fluorimetric cathepsin FRET assay kits.

    Po also highlights the company’s hydrocarbon-stapled peptides, in which the modified amino acids are artificially “stapled” together to create an alpha-helical secondary structure. This increases peptide chemical stability and may offer biological stability by making the peptide resistant to protease activity, offering protection from proteolytic enzymes. The modification may also enhance the cell permeability of short peptides, while improving their target-binding affinity.

    For luciferase-based assays, AnaSpec offers custom synthesis of peptide-aminoluciferin substrates, which are amenable for use in high-throughput screening assays. Substitution of an amino group for the 6-position hydroxyl group transforms a luciferin molecule into aminoluciferin, allowing the molecule to form amide bonds with a peptide while retaining the bioluminescent properties of luciferin.

  • Expanding Capacity

    With recent economic conditions, Peptisyntha has seen “a more discriminative funding approach” across GMP peptide programs.  “Successful drug projects seemed to have attracted partnering attention of big pharma more rapidly, while some other drug projects with higher uncertainty profiles are put on hold or discontinued altogether,” says Johan Devenyns, Ph.D., head of Solvay Peptides, the parent company of Peptisyntha.

    The company has continued to expand its capacity, with the recent completion of new QA/QC laboratories and offices at its California site. The company has also leased a fourth building on the same premises, providing space for a future expansion of its solid-phase production capacity, according to Satish Joshi, president of Peptisyntha.

    At its Brussels site, home of the company’s solution-phase manufacturing capability, Peptisyntha finished validation and took into operation new lyophilization capacity and, in April, commissioned a new pilot installation using organic electrochemical processes for the production of non-natural beta-amino acids. A recent cGMP inspection of the Brussels facility by the U.S. Food and Drug Administration for commercial peptide APIs manufactured for the U.S. market was completed successfully and generated no written or oral observations or discrepancies, according to Joshi.

    Work continues on the installation and validation of hardware and software for a manufacturing execution system that will automate a series of workflow processes involved in peptide production. “This will include automated follow-up of the flow of materials moving in and out of the company’s new warehouses and will allow a significant productivity upgrade in an environment with multiple product streams,” says Dr. Devenyns.
    According to Peptisyntha, key market trends include a growing focus on PEGylation; increasing interest in peptide drug projects in the areas of diabetes, obesity, and cancer; and more projects that may benefit from hybrid strategies that combine solid-phase and solution-phase synthetic processes.

    The PolyPeptide Group (PPL) also reports a market decline stemming from the biotech sector, with gains continuing from the pharmaceutical industry. Progress continues on PPL’s newest production site in Mumbai, and Rodney Lax, director of business development, reports that the facility will begin manufacturing generic peptides by the end of 2009.

    Corporate expansion is still under way in Scandinavia as well, and PPL has begun to look for a new facility to allow for additional growth in the South Bay region in California.

    While the market for short peptides (<10 amino acids) remains relatively stable, companies such as PPL report a rise in orders for peptides that require increasingly complex syntheses, whether due to increased length or a variety of modifications. In addition to growing demand for PEGylated peptides, Lax describes interest in complex structures that may contain more than one peptide (for activity against dual targets) or incorporate nonpeptide organic moieties.

    “I am quite upbeat about 2010,” says Lax. “A lot of companies are holding back right now waiting to see how quickly the economy recovers.”

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