Molecular model of the CRISPR-associated protein Cas9 in complex with RNA and DNA

Activity of the CRISPR–Cas9 complex (blue and pale green), a widely used tool for editing DNA (purple), can be tightly controlled thanks to the discovery of an inhibitor. Credit: Ella Maru Studio/SPL

Biological techniques

Compound stops CRISPR enzyme running amok

A small molecule is identified that puts the brakes on the Cas9 enzyme.

A chemical inhibitor of the CRISPR–Cas9 gene-editing tool could allow researchers to switch editing on and off in living cells.

CRISPR–Cas9 provides a relatively simple way to make precise changes to genomes. But the system can also make unwanted alterations, particularly if the Cas9 enzyme — which binds to and cuts DNA — remains active for long periods of time. Amit Choudhary at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and his colleagues developed molecular ‘screens’ that allowed them to sift through more than 10,000 compounds in search of those that inhibit Cas9’s activity.

That screening, followed by chemical modification of promising candidates, yielded a compound called BRD0539 that can cross cell membranes and block the normal Cas9 enzyme. The compound also dampened down the activity of another widely used research tool: a modified version of the Cas9 enzyme that is used to switch on specific genes.