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Jul 1, 2012 (Vol. 32, No. 13)

Reducing Peptide Synthesis Costs

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    According to The PolyPeptide Group, its Liquid (Solution) Phase Peptide Synthesis (LPPS) is the technology of choice for many peptides, particularly shorter peptides or structures that prevent attachment to a resin matrix.

    Peptides have long floated in a kind of no-man’s land between small molecules and proteins. Their high specificity and low tox profiles are attractive, but high production costs along with delivery and bioavailability issues have tempered drug industry enthusiasm.

    Recently, the broad rush toward biologics has rekindled biopharma’s interest in peptides and prompted peptide suppliers to seek new ways to trim production costs and tackle longer, more complex peptides.

    While Fmoc chemistry remains the backbone for most peptide synthesis, a diverse array of process optimizations and advancing instruments are helping peptide suppliers wring out production costs, improve purification, and reduce solvent waste. Bachem, for example, reported that switching from HPLC to Ultra HPLC reduced the time required for one process from 50 minutes to eight minutes and improved results. Recombinant processes are making similar strides.

    Accurately ascertaining the peptide market size is difficult; most estimates converge around $800–$900 million for the total peptide API market, with roughly half of that available to noncaptive suppliers.

    “Perhaps 20 percent of all products approved this year will be biologics, including six or more peptide products,” said Rodney Lax, Ph.D., senior director of business development, The PolyPeptide Group. “There is enormous interest in peptides.”

    Peptides International (PI) recently entered a partnership with API supplier Peptisyntha (member of the Solvay Group) for the production of research-grade peptide APIs. “It’s a nice strategic partnership and shows the confidence they have in our research capabilities,” said Mike Pennington, Ph.D., president and COO of Peptides International.

    The company emphasizes speed and quality and uses a variety of robotic systems to speed throughput, according to Dr. Pennington. “Most of these are parallel peptide synthesizers that make 50 micromoles to about 2 millimoles using, for example, 12- and 6-channel synthesizers,” he said.

    Demand from biopharma is growing, he added. “There’s a tremendous thrust for new peptide research, especially with regard to oncology, because these cell-penetrating peptide (CPPs) motifs turned out to be incredibly useful tools for delivering drugs to the inside of cells.”

    He cited antineoplastic drugs such as doxcorubicin, cisplatin, and chlorambucil, and their ability to be selectively delivered to tissues that have cancerous or neoplastic growth via these novel CPPs. “I definitely believe the API peptide manufacturing sector will have substantial growth. You can see the number of projects that are in Phase II and III clinical development.”

    Nevertheless downward price pressure characterizes the research peptide market, partly because it is less subject to regulatory control and partly because of global suppliers in markets with low labor costs. Dr. Pennington suggests a buyer-beware policy on quality.

  • Hybrid Approaches Proliferate

    One continuing trend is blurring of the line between solid-phase peptide synthesis (SPPS) and liquid- (or solution-) phase peptide synthesis (LPPS) as companies seek to combine the benefits of both approaches, noted Barry O’Connor, Ph.D., research scientist, Sekisui Medical, who presented the company’s Molecular Hiving (MH) technology at the recent “TIDES” conference.

    Traditionally LPPS offers better economies of scale for large quantities, while SPPS is faster and well suited for synthesizing longer peptides. Sekisui’s MH technology is hydrophobic tag-assisted LPPS that integrates the key advantages of SPPS for practical and highly efficient preparation of peptides. “It is applicable for the development of peptides ranging from short to long and can be easily transferred from small (g) to large scale (kg),” said Dr. O’Connor.

    In brief, peptides attached to the hydrophobic tags form concentrated reaction fields as reverse-micelles. After each reaction cycle, adding more solvent causes the growing peptide chains in the micelles to precipitate, simplifying removal before proceeding to deprotection and the next cycle.

    “An important advantage,” Dr. O’Connor explained, “is that it allows us to carry out efficient and cost-effective production of short and long peptides by using an inexpensive achiral hydrophobic tag in place of an expensive solid support. Once the tag is in place, simple peptide coupling/deprotection chemistry is utilized to deliver the desired peptides in excellent yield and high purity.”

    To demonstrate MH’s strength, Sekisui synthesized the direct thrombin inhibitor 20 mer peptide, bivalirudin, using both MH technology and SPPS for comparison. MH, after 42 steps, resulted in a total yield of 71% with crude purity of 83%, significantly superior to SPPS, which delivered a purity of only 60%. Moreover, MH’s costs were substantially less than those for SPPS, noted Dr. O’Connor.

    Another company attacking production costs and purity by blending SPPS and LPPS concepts is Ajinomoto. Daisuke Takahashi, chief, Research Institute for Bioscience Products and Fine Chemicals at Ajinomoto, described the company’s new approach.

    Ajinomoto’s AjiPhase process “overcomes the disadvantages of traditional LPPS yet retains the benefits of lower cost, higher quality, and easier scale-up compared to SPPS,” said Takahashi. “We have applied this technology to the synthesis of a variety of peptides including larger than 40 mers, cyclized, and conjugated peptides in high volumes. The significant reductions in production costs and purification load compared to SPPS have been demonstrated.”

    AjiPhase’s liquid-phase advancements—including patented anchors, unique and efficient deprotection, and scavenger agents—eliminate the isolation, crystallization, and purification steps between couplings, according to Takahashi. The higher purity of crude peptide product created by AjiPhase lessens the purification load and helps reduce the development time normally associated with LPPS, while generating a greater yield of higher-purity peptides, he said.

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