The deal remains subject to approval from the relevant antitrust authorities and the fulfillment of closing conditions under the share purchase agreement. AGC, a world-leading manufacturer of glass, chemicals and high-tech materials, has announced that it has entered into an agreement with Boehringer Ingelheim to acquire Malgrat Pharma Chemicals, S. MPC is a subsidiary of Boehringer Ingelheim that manufactures synthetic pharmaceutical active ingredients 1 for the group. MPC has vast experience manufacturing cGMP 3 -compliant commercialized synthetic pharmaceuticals as well as compounds in clinical development on a range of scales.
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FacilitiesVIDEO ON THE TOPIC: Synthetic Biology: Production of Novel Antibiotics - Eriko Takano
Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. To date, most successful commercial products were carefully selected for their manufacturing via biological synthesis.
As discussed in the preceding chapter, a large degree of chemical space is already known to be available for chemical manufacturing. The vision of the future put forth herein is one where biological synthesis and engineering and chemical synthesis and engineering are on par with one another for chemical manufacturing.
The recommendations and roadmap goals outlined throughout this report were all conceived in the context of this overarching vision and are designed with the understanding that, in order for the industrialization of biology to be realized, the use of biological and chemical routes must be thought of as equals. That is not to say that each would be used interchangeably, but that biological routes would be included the same way individual chemical reactions are considered when developing a synthetic route.
Determining whether both biological and chemical routes should be set on equal footing and understanding the potential diversity of chemical products that could be produced are critical to the industrialization of biology.
The majority of this chapter is devoted to answering these questions. The industrialization of biology offers prospects not only for new commercial production and process methods but also for the opening. As discussed in Chapter 4 , enzyme- or cell-based synthetic approaches can provide compounds ranging from drop-in replacements—made via processes with economic or environmental advantages over previous synthetic methods—to new structures with improved function or performance relative to their chemical precursors.
Targets at either end of this spectrum are subject to very different factors with respect to technological and economic factors influencing their development Figure Both commodity and specialty chemicals can be approached using biological methods but should take advantage of the unique properties of living systems.
For commodity chemicals, targets need to add economic value to the starting carbon source e. These types of targets can provide both economic and environmental benefits via the ability of cells to utilize biomass-derived carbon sources, grow in aqueous media, and carry out multistep transformation of substrate to product in a single reactor.
Specialty or fine chemical targets yield more flexibility in approach and cost of manufacture based on their higher value. Indeed for many complex natural products, there may be no existing chemical method for their commercial manufacture. As such, a biological route can provide new access to the target or a semisynthetic intermediate. In addition to multistep cellular transformations, single enzyme-based transformations may also be important in this area because the utilization of enzymatic regio- and stereoselectivity can greatly streamline a chemical process.
The continued development of biotechnology related to chemical synthesis also enables new routes to discovery when combined with the more mature area of chemical synthesis, because it allows opportunities to mix orthogonal structural space. In this regard, living systems produce a wide range of compounds that often demonstrate relatively low structural overlap to those produced via synthetic methods Figure Much of this divergence in structure arises naturally from differences in building block availability and assembly.
In general, synthetic compounds are ultimately derived from petrochemical sources with substitution patterns controlled by the selectivity of chemical reagents but can take advantage of a broader coverage of elemental composition, functional groups, and reaction space.
In contrast, large classes of biological metabolites often share a biosynthetic logic in their assembly but can utilize the selectivity of enzymes to produce highly complex structures. As such, the development of methods for combining biological and synthetic chemistry could. Some of the current targets of chemical manufacturing are identified. Natural products and their derivatives remain an important resource for the discovery of new bioactive compounds.
They represent a significant portion of new chemical entities while also playing an important role in the identification of druggable targets and pathways for development of synthetic compounds. As such, it is estimated that it is several orders of magnitude more likely that a natural product will bind a cellular target compared to a synthetic compound.
However, the use of natural products as lead compounds is quite challenging, because they are difficult to synthesize and structurally optimize for appropriate pharmacokinetic behavior. As such, natural products routinely remain underutilized in the drug discovery pipeline, and advances in biotechnology on many different fronts could greatly alter this landscape. It is widely accepted that natural products contain an enormous structural diversity. As previously discussed, this structural diversity typically accesses structural space outside of chemically synthesized compound libraries, yet poises natural products for macromolecular target binding.
Thus, the inclusion of new natural product structures and their pharmacophores is important for expanding the available space for discovery.
However, there are several roadblocks to achieving this goal: most natural products are produced at extremely low yield in their native host; the majority of genes encoding the production of natural products are silent, that is, displaying no detectable phenotype; and most environmental isolates are not culturable under laboratory conditions.
Thus, new methods of moving from gene sequence to product are important and could potentially be provided both by the ability to synthesize and express large sets of genes in model hosts and by rapid approaches to domesticate environmental hosts.
While the complexity of natural product structures serves as an advantage in their use as lead compounds, it rapidly becomes a disadvantage given that most lead compounds need to be optimized for proper potency, cross-reactivity, and pharmacokinetic behavior. Semisynthetic approaches, or the direct chemical modification of a natural product or biosynthetic intermediate, are limited in their ability to achieve a broad range of structural transformations of the natural product given their functional group density and lability to harsh chemical reaction conditions.
Thus, enzymatic or biosynthetic modifications can provide a new route into structural diversification of natural products for tuning their performance as drugs. In this regard, the identification and characterization of tailoring enzymes that may oxidize, cross-link, or ligate on new groups to core structures are useful.
In addition, methods to feed in different building blocks to the biosynthetic machinery can generate much-needed variations in the core structure. Advances in manipulating core structure and tailoring can further help to create diversity by introducing orthogonal chemical handles e. Beyond the exploration of natural products classes with known genetic signatures, such as polyketides, nonribosomal peptides, and isoprenoids, there are many structural cores that have yet to be identified or genetically annotated.
Among these are nitrogen-rich compounds of varied structure, including alkaloids, which are needed to augment our pool of compounds, as the more well-characterized classes of natural products tend to be oxygen rich e.
Modified peptides, both ribosomally and nonribosomally encoded, also represent interesting families for further characterization. Improvements in gene prediction, chromosome modification, host domestication, and small-molecule analysis can aid in this endeavor. For the development of advanced molecules, the relatively new interface between synthetic chemistry and biology needs to be further enlarged because synergy between these two areas can greatly accelerate the discovery process.
For example, microbial fermentation can generate previously untapped monomers for polymer production, but the synthesis and characterization of the resulting materials is equally essential for identifying new properties or functions.
Conversely, the analysis of. Research directions in this area could include but are not limited to engineering enzymes or pathways for the biological production of complex building blocks, stereo- and regioselective transformation of synthetic building blocks, reactions involving key elements or functional groups, and catalysis of new C-C bond-making reactions. In addition, computational tools to combine biological and synthetic reaction space to analyze the efficiency of different hybrid preparation routes are also necessary to identify specific paths forward for further development.
Engineering the Production of Complex Building Blocks. Building blocks with a high density of stereocenters or functional groups can often be derived from biological sources. Some examples include isoprenoids, sugars, and other classes of metabolites, which are used as synthetic starting materials but also can affect the price and availability of the final product. One example was previously presented for the production of artemisinin from a microbially derived semisynthetic intermediate. In this case, both the intermediate and the target compounds are natural products and synthetic chemistry is used to scale up a biologically difficult reaction that ultimately opens access to a low-cost antimalarial drug.
A different type of advancement in this area can be illustrated in the commercial synthesis of oseltamivir Tamiflu , a synthetic antiviral compound prescribed for avian flu that is made from shikimic acid. This biosynthetic intermediate is produced by microbes and plants but at such low levels that its availability controls that of Tamiflu.
As a result, a strain of E. Without using the innate stereochemistry of shikimic acid, the synthesis of Tamiflu would likely require several steps resulting in higher prices and decreased availability. Beyond traditional natural products, biological systems are also uniquely poised for the generation of other types of structures with challenges of regioselectivity and stereoselectivity.
One example is represented by polysaccharides, which can be important modifiers of bioactive agents. Their chemical synthesis requires extensive and laborious protection and deprotection routines to achieve regioselective assembly but can potentially be put together instead from their unprotected parental sugars using glycosyl transferase enzymes. The ability to take these routes and use computational analysis or software to identify these points of overlap rather than relying on human insight could greatly accelerate similar projects.
By extension, large-scale analysis of various synthetic routes could also help to identify classes of molecules or patterns of substitution that could be produced using biological systems as useful synthetic building blocks. Enzymes excel at selective transformations and have been used as reagents for individual transformations of synthetic intermediates when chemical reagents are difficult to optimize for a particular reaction.
In many cases, the adoption of an enzymatic step could streamline the synthetic route, which may utilize a number of additional steps in order to avoid a particularly challenging problem in asymmetric catalysis. In this case, families of enzymes, such as ketoreductases, esterases, peptidases, and transaminases, have been well developed for these applications.
Thus, the identification and implementation of new target enzyme families and transformations could greatly accelerate advances in this area. Compared to the chemical reaction scope, cells typically use a smaller set of functional groups and lower diversity of C-C bond-forming reactions, because enzymes can use substrate and product selectivity to form the correct bond amidst many different possibilities.
Thus, an interesting area of development could incorporate enzymes to install rarer elements or synthetic functional groups for function or as synthetic handles for downstream chemical catalysis. In addition, new enzyme classes could also be evolved to catalyze C-C bond coupling reactions from synthetic building blocks. One example where synthesis has inspired the development of new reaction chemistry involves the engineering of cytochrome Ps for the insertion of C or N rather than O to form cyclopropane or aziridine rings.
Polymers are organic macromolecules made of repeating monomer units that are valued for their tunable functional and structural properties. Indeed, polymers are used for a broad range of applications, from use as plastics, rubbers, fibers, and paints to controlled drug release and electronic displays. They are derived from biological sources, such as natural rubber, silk, and cellulose, as well as synthetic origins, such as polyethylene, polystyrene, nylon, silicone, and polyvinyl chloride.
Polymer properties are controlled by many variables, including monomer structure, bonding between monomers, tacticity, average molecular weight, polydispersity, and branching for homopolymers.
Co-polymers made up of more than one monomer type expand this range even further to include attributes such as monomer arrangement periodic, statistical, or random or co-block characteristics.
These structural features influence intra- and interchain microstructure that in turn control bulk material properties that are important for function, such as melting temperature, crystallinity, glass transition, tensile strength and elasticity, transport behavior, and electronic response. The relationship between chemical and materials properties has been well explored but remains challenging to predict from a new monomer given the breadth of different polymers that can be accessed.
At this time, many of the commodity polymers are constructed from building blocks that can be prepared from readily available petrochemical sources. However, living systems provide a vast array of bifunctional compounds that can be used as monomers, the majority of which have yet to be tapped for polymer synthesis. This section covers opportunities in metabolic engineering for existing and new monomers and polymers. One approach is the direct replacement of existing monomers derived from petrochemical sources with the same structure made by microbial fermentation.
A key advantage in this strategy is that a drop-in replacement already has a current market demand. However, two major chal-. Other examples of monomers in the development pipeline at this time are butadiene from dehydration of 1,4-butanediol, Genomatica , 86 acrylic acid from dehydration of 3-hydroxypropionic acid, Cargill, OPXBIO; or lactate, Myriant , 87 and isoprene Dupont and Goodyear.
All three of these monomers are targeted toward large-volume markets. Other similar targets can be identified by examining the commodity chemicals market and could be prioritized by their biosynthetic complexity as well as the range of polymer products, because niche markets could potentially be easier to move toward biosourced monomers. Another approach is the development of new monomers to produce novel polymers. Although the market for these new monomers is more difficult to characterize, they do not need to directly compete with an existing product made through a mature process.
This approach also allows polymer chemists to explore greater chemical space to improve the material properties of polymers or to discover entirely new functions. In general, many commercial polymers have been developed from readily available petrochemical feedstocks and optimized for their intended application by controlling various parameters as discussed above.
As such, compounds falling into the same chemical class as known monomer feedstocks, but with different substitution patterns, could be funneled into the same polymerization pipeline but impart altered properties to homo- and co-polymers. However, the new microbial process for its production enabled greater access to this monomer and led to the development of new polymers that have earned significant market share.
A second example that highlights the interplay between chemistry and biology is polylactic acid or polylactide, PLA made from the microbially sourced lactic acid monomer, developed by NatureWorks. The underlying biology of these systems involved in controlling important parameters including chain length and polydispersity is quite complex and remains insufficiently understood for rapid engineering. As a result, the polymer properties of bioengineered PHAs were difficult to tune compared to synthetic polyesters made from mature chemical processes.
NatureWorks developed instead a process based on the chemical polymerization of lactate, which is also a 3-hydroxyacid even though it is not typically a physiological monomer for PHA biosynthesis.
Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. To date, most successful commercial products were carefully selected for their manufacturing via biological synthesis. As discussed in the preceding chapter, a large degree of chemical space is already known to be available for chemical manufacturing.
A Smarter – and Synthetic – Workflow for Bioengineering
Saponins are widely distributed plant natural products with vast structural and functional diversity. They are typically composed of a hydrophobic aglycone, which is extensively decorated with functional groups prior to the addition of hydrophilic sugar moieties, to result in surface-active amphipathic compounds. The saponins are broadly classified as triterpenoids, steroids or steroidal glycoalkaloids, based on the aglycone structure from which they are derived. The saponins and their biosynthetic intermediates display a variety of biological activities of interest to the pharmaceutical, cosmetic and food sectors. Although their relevance in industrial applications has long been recognized, their role in plants is underexplored. Recent research on modulating native pathway flux in saponin biosynthesis has demonstrated the roles of saponins and their biosynthetic intermediates in plant growth and development. Here, we review the literature on the effects of these molecules on plant physiology, which collectively implicate them in plant primary processes.
Current Uses of Synthetic Biology
Population growth, climate change, and dwindling finite resources are amongst the major challenges which are facing the planet. Requirements for food, materials, water, and energy will soon exceed capacity. Green biotechnology, fueled by recent plant synthetic biology breakthroughs, may offer solutions. This review summarizes current progress towards robust and predictable engineering of plants. I then discuss applications from the lab and field, with a focus on bioenergy, biomaterials, and medicine. This review summarizes the current state of research in plant synthetic biology, and how it is being applied to two topics: renewable fuels and chemicals, and medicine. Major advances in agronomic practices and plant breeding the Green Revolution resulted in vastly increased crop yields but needed large inputs of irrigated water, synthetic nitrogen fertilizers, and other nutrients.SEE VIDEO BY TOPIC: Protein Synthesis (Updated)
Isoprene is an important commodity chemical used in a variety of applications, including the production of synthetic rubber. Isoprene is naturally produced by nearly all living things including humans, plants and bacteria ; the metabolite dimethylallyl pyrophosphate is converted into isoprene by the enzyme isoprene synthase. But the gene encoding the isoprene synthase enzyme has only been identified in plants such as rubber trees, making natural rubber a limited resource. Currently, synthetic rubber is derived entirely from petrochemical sources. Although plant enzymes can be expressed in microorganisms through gene transfer it is a long and cumbersome process, as plant genes contain introns and their sequences are not optimized for microorganisms. DNA synthesis and DNA sequencing have enabled the construction and rapid characterization of metabolically engineered microorganism strains to produce isoprene. Synthetic biology has enabled the construction of a gene that encodes the same amino acid sequence as the plant enzyme but that is optimized for expression in the engineered microorganism of choice. This method has provided massively parallel throughput which has made it possible to identify and track genetic variation among the various strains, providing insights into why some strains are better than others.
The transaction had been previously announced on December 4, With the addition of MPC, it has now become possible for AGC to manufacture and process intermediates for synthetic pharmaceuticals all the way through active ingredients, in Europe. AGC had been serving pharmaceutical customers with its original fluorine technology and extensive experience in in-house drug discovery from Japan, and this will be an additional physical location to serve from. MPC both meets cGMP 2 standards, as well as having a long history as a production site with strong track record. Its production lines are designed to handle diverse scales needed, from development phase to commercial stage pharmaceuticals. With this acquisition, AGC hopes to increase its presence in the European market, where demand is forecasted to continue at a significant growth rate, and further expand its CDMO 3 synthetic pharmaceuticals business for customers around the world. Under its AGC plus management policy, the AGC Group places the life sciences business as a strategic business, and is aiming to generate sales of over 65 billion yen in , and over billion yen in With this step now complete, the AGC group will continue to proactively search for next opportunities and to invest in its synthetic and bio pharmaceutical businesses, so as to better serve through its capabilities, the pharmaceutical industry and the patients and wider society they serve in turn. Based on more than a century of technical innovation, the AGC Group has developed a wide range of cutting-edge products. The AGC Group employs some 50, people worldwide and generates annual sales of approximately 1. For more information, please visit www.
Harnessing evolutionary diversification of primary metabolism for plant synthetic biology
Plant-based chemistry uses biomass resources as an alternative to fossil resources for the manufacturing of products and materials. Plant-based chemistry is a branch of chemistry in which biomass wholly or partially replaces fossil resources oil, natural gas and coal to manufacture products. It is thus possible to use biomass to manufacture biobased products and materials of varying degrees of sophistication, such as:. Plant-based chemistry can also use co-products, i. The search for optimum use of biomass in an integrated system has led to the creation of biorefineries. Biorefineries represent an industrial tool which, on a given site, isolates, processes and reclaims each component of the biomass. According to the biorefinery concept, the biomass must be transformed and valorised. In Europe, there are 34 biorefineries. Plant-based chemical intermediates biobased products are used in numerous sectors such as detergents, cosmetics, the automobile industry, aviation, packaging, plastics manufacturing, construction and paints.
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Phytochemicals are important sources for the discovery and development of agricultural and pharmaceutical compounds, such as pesticides and medicines. However, these compounds are typically present in low abundance in nature, and the biosynthetic pathways for most phytochemicals are not fully elucidated. Heterologous production of phytochemicals in plant, bacterial, and yeast hosts has been pursued as a potential approach to address sourcing issues associated with many valuable phytochemicals, and more recently has been utilized as a tool to aid in the elucidation of plant biosynthetic pathways. Due to the structural complexity of certain phytochemicals and the associated biosynthetic pathways, reconstitution of plant pathways in heterologous hosts can encounter numerous challenges. Synthetic biology approaches have been developed to address these challenges in areas such as precise control over heterologous gene expression, improving functional expression of heterologous enzymes, and modifying central metabolism to increase the supply of precursor compounds into the pathway.
Plants produce numerous natural products that are essential to both plant and human physiology. Recent identification of genes and enzymes involved in their biosynthesis now provides exciting opportunities to reconstruct plant natural product pathways in heterologous systems through synthetic biology.
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The new capacity is set to come online in October AGC began developing and manufacturing pharmaceutical and agrochemical intermediates and active ingredients on a contract basis in the s. While AGC has to date mainly provided CDMO services for in the development stage of new drugs, this expansion will give AGC the end-to-end capability to produce commercial drugs too, allowing it to deliver more advanced one-stop solutions.
Process chemistry is the arm of pharmaceutical chemistry concerned with the development and optimization of a synthetic scheme and pilot plant procedure to manufacture compounds for the drug development phase. Process chemistry is distinguished from medicinal chemistry , which is the arm of pharmaceutical chemistry tasked with designing and synthesizing molecules on small scale in the early drug discovery phase.