PT  - JOURNAL ARTICLE
AU  - Ragotte, Robert J.
AU  - Liang, Huazhu
AU  - Berman, Jacob M.
AU  - Glögl, Matthias
AU  - Schramek, Daniel
AU  - Melnyk, Roman A.
AU  - Baker, David
TI  - De novo designed inhibitor confers protection against lethal toxic shock
AID  - 10.1101/2024.08.23.608890
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.08.23.608890
4099  - http://biorxiv.org/content/early/2024/08/24/2024.08.23.608890.short
4100  - http://biorxiv.org/content/early/2024/08/24/2024.08.23.608890.full
AB  - Paeniclostridium sordellii causes a toxic shock syndrome with a mortality rate of nearly 70%, primarily affecting postpartum and post-abortive women. This disease is driven by the production of the P. sordellii lethal toxin, TcsL, for which there are currently no effective treatments. We used a protein diffusion model, RFdiffusion, to design high affinity TcsL inhibitors. From a very small set of 48 starting designs and 48 additional sequence optimized designs, we developed a potent inhibitor with <100 pM affinity that protects mice prophylactically and therapeutically (post exposure) from lung edema and death in a stringent lethal challenge model. This inhibitor, which can be lyophilized without any loss of activity, is a promising therapeutic candidate for this rare but deadly disease, and our results highlight the ability of deep learning-based protein design to rapidly generate biologics with potential clinical utility.Competing Interest StatementRJR, HL, MG, RAM and DB are inventors on a provisional patent application covering the inventions described in this paper.