De novo design of potent CRISPR-Cas13 inhibitors
- Author(s)
- Taveneau, C; Chai, HX; D'Silva, J; Bamert, RS; Chen, H; Hayes, BK; Calvert, RW; Purcell, J; Curwen, DJ; Munder, F; Martin, LL; Barr, JJ; Rosenbluh, J; Fareh, M; Grinter, R; Knott, GJ;
- Journal Title
- Nature Chemical Biology
- Publication Type
- Online publication before print
- Abstract
- CRISPR-Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)-phage-derived inhibitors that regulate CRISPR-Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR-Cas activity. Here, using Leptotrichia buccalis CRISPR-Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR-Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR-Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR-Cas tools in diverse applications across research, medicine, agriculture and microbiology.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41589-025-02136-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s41589-025-02136-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-02-03 06:11:43
Last Modified: 2026-02-03 06:11:50