Enzymes create pharmaceuticals

Drug-drug interactions have always been major concerns to the pharmaceutical industry. Several prominent drugs were withdrawn from the market because of serious adverse events related to drug-drug interactions. These interactions create problems for clinicians and patients and economic losses for pharmaceutical manufacturers. For this reason, pharmaceutical companies screen for enzyme inhibition and induction at the discovery stage. 

The production of enantiomerically pure compounds is of great importance to the chemical and pharmaceutical industries. Enzymes are chiral catalysts by nature and they have incredible potential for creating enantiomerically pure products. However, many existing natural enzymes show low degrees of enantioselectivity, which requires further improvement by protein design. 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

In 1960, at the general assembly of the International Pharmaceutical Federation (FIP), the obsolescence of various national pharmacopeial methods for assaying pharmaceutical enzymes was demonstrated. An international commission on pharmaceutical enzymes was created to deal with this unsatisfactory situation and develop improved assay methods and guidelines for the preparation of pharmaceutical enzyme reference materials. The Center for Standards has a coordination function in organizing collaborative enzyme assays between academic, industrial, and national pharmaceutical control laboratories and in distributing FIP pharmaceutical enzyme standards. Since 1960, many FIP assay methods and standard preparations have been adopted by national and international pharmacopeias, such as the European Pharmacopoeia. The ultimate goal is to provide official, preferentially nonempirical, standardized assay methods by which comparison of commercially available pharmaceutical enzymes is made possible. The most desirable situation would be an international uniformity of enzyme standards and assay methods, which would allow physicians and clinicians to unambiguously compare the potencies of commercially available enzyme products. 

Although there is much to be optimistic about the future of protein pharmaceuticals, there are still many unique problems with their development, production, and delivery. Among the more obvious problems with protein drugs is the fact that they are much more delicate than small-molecule drugs. Proteins such as hormones, antibodies, and enzymes cannot normally be compounded or pressed into dry pills or emulsified or concentrated into tinctures. This type of conventional pharmaceutical manufacturing and formulation would destroy the activity of most protein pharmaceuticals. Similarly most peptide hormones, antibodies, and enzymes cannot be stored indefinitely at room temperatures in nonsterile containers instead they must be kept in a cool, dark, aqueous, sterile environment for no more than a few weeks. These limitations to protein preparation and formulation have created a significant challenge to pharmaceutical chemists. Potential solutions to these problems are discussed in Chapter 4 of this book. 

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