Lead optimisation of polyketide-based natural products: strategies, technologies and case-studies

There is a noticeable shift in the pharmaceutical industry away from high-throughput screening of large libraries of compounds against single isolated targets, towards the application of phenotypic screening. In concert with this has been the realization that the typical small molecule libraries are insufficient to query these 'high-content' biology approaches effectively. This observation has ignited an interest in more 'high-content' chemistries to provide screening libraries, an application for which natural products are ideally suited. Results from these screening campaigns typically reveal prominent natural product hits, with polyketides well represented amongst these. These hits represent either excellent chemical genetics tool compounds or a challenge for drug discovery.

Strategies and technologies for converting these polyketide leads into candidate drugs will be presented along with case studies from Biotica's work, including rapamycin and FK506.

Finally the application of these technologies to sanglifehrin A will be discussed. Sanglifehrin A is a cyclophilin-binding polyketide natural product and from this lead we have discovered a series of compounds, the sangamides. These compounds have been preclinically characterised as host-targeted therapies for chronic HCV infection.