# Efficient and Selective Biosynthesis of a Precursor-Directed FK506 Analogue: Paving the Way for Click Chemistry

## TL;DR

Scientists created a new version of the drug FK506 with a chemical group that allows for easier chemical modifications, which could help improve drug development.

## Contribution

A new chemobiosynthetic method to produce an FK506 analogue with a propargyl group for click chemistry.

## Key findings

- The new FK506 analogue has a propargyl group at carbon 21 for click chemistry compatibility.
- The analogue shows reduced immunosuppression and cytotoxicity compared to FK506.
- The method may be applicable to other polyketide-derived drugs.

## Abstract

The medically important immunosuppressant
FK506 is a
structurally
complex macrolactone biosynthesized by a combined polyketide synthase
and a nonribosomal peptide synthetase enzyme complex. Its acyltransferase
domain 4 (AT4) selects an unusual extender unit, resulting in an allyl
moiety on carbon 21 of the macrolactone backbone. Based on the AT4
domain, chemobiosynthetic processes have been developed that enable
the introduction of diverse moieties at the carbon 21 position. However,
the novel moieties that were introduced into the polyketide backbone
are chemically inert. Reported here is a novel and efficient chemobiosynthetic
approach that ensures high titer of an FK506 analogue containing a
propargyl moiety. The novel FK506 analogue displays lower immunosuppression
activity than FK506 with significantly reduced cytotoxicity. More
importantly, the propargyl moiety contains a terminal alkyl group,
which makes click chemistry reactions possible; this approach may
potentially be translated to other medically important drugs of polyketide
origin.