In the world of protein degradation, sometimes a spanner in the works isn’t an inconvenience but the desired result. Paris-based Enodia Therapeutics has launched out of France’s Pasteur Institute and the Argobio Studio to design small molecules that strategically throw a wrench in the processing of undesired proteins.
Protein synthesis involves multiple steps that scientists can target to get rid of unwanted proteins. Enodia focuses on one of the earlier steps. After proteins are created by a ribosome, the next step is processing by the endoplasmic reticulum, an organelle that gets nascent proteins ready to be transported to their final destinations. The gateway to the endoplasmic reticulum is the Sec61 translocon, a channel that recognizes proteins and grants them entry.
Enodia’s scientific cofounder, Caroline Demangel, identified this channel as a possible therapeutic target for cancer; she was inspired by the naturally occurring bacterial toxin mycolactone, which blocks Sec61—and thus most proteins—from getting into the endoplasmic reticulum (EMBO Mol. Med. 2022, DOI: 10.15252/emmm.202114740). Demangel and others at the institute discovered that blocking this channel induces lethal stress in some cells because of all the misfolded proteins that accumulate.
Mycolactone is fairly nonspecific, allowing only a small group of proteins to get through Sec61 at all. But Enodia is trying to make Sec61 blockers that block only certain proteins from entering the endoplasmic reticulum. Instead of letting the channel get gummed up for every protein, Enodia is using artificial intelligence to design small molecules that recognize a peptide “zip code” on certain proteins and stop only them from getting through. These denied proteins could then be degraded by the proteasome, the cell’s trash compactor.
While protein degradation is not a new concept in medicine, Enodia’s strategy differs from other degradation methods in two important ways. First, Enodia’s small molecules are meant to target proteins earlier in their synthesis pathway, while degraders such as proteolysis-targeting chimeras (PROTACs) and molecular glues target them after they have been fully processed and secreted.
Second, it’s possible that one of Enodia’s designed Sec61 blockers could inhibit two proteins at once if it can recognize two signal peptides, while PROTACs and molecular glues can target only one protein at one time. But Enodia hasn’t definitively proven this in the lab.
While Demangel’s group initially focused on cancer, Enodia’s goal now is “to target one specific protein for one indication in autoimmunity and inflammation,” says Yves Ribeill, the firm’s CEO. Enodia, which was incubated by the biotech start-up studio Argobio and the Pasteur Institute, is raising a series A funding round. In the future, it will look for a pharmaceutical industry partner to develop a drug candidate.