Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

TL;DR

This paper shows how P450 enzymes can be used to modify drug-like compounds efficiently, speeding up drug discovery by avoiding complex chemical synthesis.

Contribution

The novel use of the PolyCYPs kit for late-stage hydroxylation and scalable biotransformation in drug discovery is demonstrated.

Findings

Late-stage hydroxylation of compounds was achieved using the PolyCYPs screening kit.

Biotransformed compounds showed biological activity against several pathogens.

Biosynthesis of a lead compound required fewer steps than traditional methods.

Abstract

Herein, we demonstrate the use of a commercially available
enzymatic
kit to achieve late-stage hydroxylation of biologically relevant compounds
by using the PolyCYPs screening kit. A selection of promising biotransformations
were scaled up, products isolated, and structures elucidated. Isolated
compounds were screened against a range of pathogens, namely, Schistosoma mansoni, Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei to obtain biological data. This
approach has allowed data generation more efficiently than the chemical
synthesis of the same molecules. Importantly, it has been demonstrated
that production of hits of interest can also be scaled up to enable
further study. We also demonstrate the biosynthetic synthesis of a
lead compound in fewer steps than using standard synthetic chemistry,
offering faster access to compounds for screening or further transformation.
This approach has the potential to save time and resources in a drug
discovery program, by reducing the necessity to synthesize late-stage
intermediates and develop new chemistry.

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