A history of recombinant protein technology in small molecule drug discovery

28 October 2014  •  Author(s): Rick Davies, Associate Director, AstraZeneca / Ian Hardern, Senior Research Scientist, AstraZeneca / Ross Overman, Associate Principal Scientist, AstraZeneca

Recombinant protein

Recombinant protein production is a prerequisite and essential component of most modern small molecule drug discovery programs. Target proteins are required to underpin screening, structural and mechanistic studies providing data that drives chemical design. From the initial establishment of recombinant protein production in the pharmaceutical industry in the 1980s, systems and technologies have evolved in step with developments in other areas to enable rapid production of many different target proteins, and their variants, specifically designed for their end use. This review describes the evolution of recombinant protein production over the past 30 years, tracking changes in technologies and working practices in relation to landmark changes in drug discovery strategies over that period.

Rise of the recombinant protein expression systems

Throughout the 1980s the development of key technologies enabling recombinant protein production progressed rapidly. However, in the pharmaceutical industry, protein targets were still largely extracted and purified from animal tissue. Consequently, many projects were driven by data that was derived using proteins from non-human species and the throughput of many assays was limited by the amount of protein which could be purified. Many batches of protein were typically required to underpin the project, and batch-to-batch variability was a frequent issue. The situation changed in the early ‘80s with the establishment and commercialisation of automated Edman sequencers1. This new technology provided the opportunity to generate amino acid sequences from proteins previously isolated by classical biochemical purification from animal tissue sources. Sequence information could then be used to design probes to allow cloning of human genes. This was a labour-intensive process but did enable the generation of human genes which could be inserted into an ever increasing set of emerging vectors for different recombinant expression systems.

Following the first recombinant expression in Escherichia coli, which took place in 1976 when scientists at Genentech – the first genetic engineering company – produced the human protein Somatostatin2, protein production systems that used bacteria continued to improve. Eukaryotic protein expression systems started to be developed, including the insect cell system that utilised baculovirus3 and the Pichia pastoris4 yeast expression system, providing the opportunity for more complex, glycosylated protein production.

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