Biocatalysis to generate next generation Protides

Introduction

Nucleoside analogues are a class of agents which include drugs for cancer, rheumatoid diseases, and even bacterial infections. They are variably effective however, and during delivery, there are multiple stages where resistance may occur. ProTide technology - phosphoramidate modification of nucleosides – have revolutionised anti-viral therapy in Hepatitis C and HIV. Sofosbuvir, used in the treatment of HCV, is the biggest revenue generator of any new therapy in history (US$22billion).

ProTides are a successful strategy, but have so far only been produced using traditional synthetic organic chemistry, and several promising leads remain elusive due to the difficulties in making them.

Challenge

Key challenges in the design and synthesis of nucleoside and nucleotide analogues include the high resource requirements (i.e. materials and energy that are required to synthesize them), low yields and the inability to generate certain desirable structures within the analogues via traditional synthetic chemistry routes.

Solution

Innovation funding of £100k from IBioIC enabled NuCana to work with Dr Czekster at the University of St Andrews on a project to combine organic synthesis and biocatalysis to generate completely novel ProTide compounds with possible activity as anti-viral or anti-cancer agents.

Nucana provided guidance on molecule generation as well as analysis tools through their mass spectrometry and chemistry capabilities.

Dr Czekster developed an enzyme based approach to produce novel ProTide analogues at reduced material and energy cost. The team at St Andrews characterised enzyme substrate scope and rationally engineered enzymes to produce a library of over 50 unprecedented compounds. For the majority of these, no chemical synthetic route is available, and biocatalysis using a single enzyme catalyst provided a facile way of production.

Outcome

This successful project delivered proof of principle that will open the door to new manufacturing tool which may provide more efficient routes of synthesis for Nucana’s existing and future ProTides, with the potential to significantly reduce manufacturing costs while increasing yield and using a more environmentally friendly process.

The project also enabled the company to produce specific nucleoside building blocks that could not be produced using traditional synthetic chemistry methods.