Biocatalysis is a valued approach in producing intermediates and APIs of desired stereoselectivity. In building their toolboxes, companies are expanding their offerings in biocatalysts through organic growth, industrial partnerships, and academic collaborations. For example, in May 2011, Almac launched its selectAZyme brand of biocatalysts, including reductases, transaminases, hydrolases, and nitrilases for use in synthesizing APIs and fine chemicals, including chiral compounds. The selectAZyme service also provides metabolite synthesis for oxidative and glycosylated products.The launch of the selectAZyme line of biocatalysts follows Almac's $4-million investment in biocatalysis R&D. Research areas include new biocatalytic platforms for producing chiral intermediates, hyperactivation of biocatalysts for reducing enzyme loadings, developing drivers for cofactor recycling, and mitigating problems with equilibriums. In 2009, the company also launched carbonyl reductase, transaminase, hydrolase, nitrilase, and nitrile hydratase enzyme-screening kits.
As an example of biocatalysis at work, Almac carried out preliminary screening to show that a carbonyl reductase (CRED) bioreduction could replace a resolution for preparing a chiral alcohol. After identifying a CRED at small scale, the company scaled up production and integrated the biocatalytic approach into the API process-development program and manufactured 30 kg for Phase I clinical trials, according to an Almac Oct. 7, 2010, press release.
In December 2010, DSM Pharmaceutical Products, the custom manufacturing organization of DSM, formed a license agreement with c-LEcta, an industrial biotechnology company. The agreement grants DSM rights to c-LEcta's proprietary alcohol dehydrogenases for enzyme-screening programs and for developing manufacturing routes for APIs and intermediates. Alcohol dehydrogenases are used to synthesize chiral alcohols from ketones.
In September 2010, DSM launched InnoSyn, a route-screening service, which applies tools such as biocatalysis, homogeneous catalysis, and continuous chemistry using microreactors to screen catalysts for feasibility studies for chemocatalytic and biocatalytic steps. The company earlier had introduced new enzymes, such as pig liver esterase (i.e., pharmaPLE), lyases, transaminases, dehydrogenases and homogeneous catalysts for asymmetric hydrogenations, aromatic substitutions, and oxidations.
In January 2011, the biocatalysis firm Codexis and DSM Pharmaceutical Products formed an enzyme-supply agreement. The agreement grants DSM rights to use Codexis's custom biocatalysts and services and secures a supply of Codexis enzymes for commercialization of pharmaceutical manufacturing routes developed by DMS's InnoSyn route-scouting service. In October 2010, Codexis expanded its offerings in biocatalysis by introducing screening kits for a subset of the range of biocatalysts it offers. The kits contain 24 enzymes from Codexis's collection of biocatalyst variants from two enzyme classes: ketoreductase and transaminase.
Codexis recently formed several biocatalysis partnerships with pharmaceutical companies. In May 2011, the company successfully completed technology transfer of custom biocatalysts for the manufacture of three undisclosed pharmaceutical products to Teva Pharmaceutical Industries. Two products were transferred to pilot manufacturing, and a third to full-scale commercial manufacturing. The original agreements covering the development of these processes were signed in 2009. In January 2011, Codexis formed a collaboration with Dainippon Sumitomo Pharma (DSP) under which Codexis is supplying biocatalysis screening products and services to DSP for use in selected undisclosed therapeutic products in its development pipeline.
In 2010, researchers at Merck & Co. and Codexis reported on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the active ingredient in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The researchers started from an (R)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing (1–3).