The “Pharmacological Protein Inactivation by Folding Intermediate Targeting” (PPI-FIT) technology, of which Sibylla is the exclusive licensee, is a paradigm shift in rational drug design. The basic task of drug design is to find a small molecule able to bind to a biological target to modulate its activity. So far, almost all rational drug design approaches have focused on the native structure of the target protein. Sibylla Biotech paves the way for a completely different strategy: targeting the protein while it is still folding.
What is folding? Every protein is born as a linear chain of units (amino acids) linked each to the next like the pearls in a necklace. When synthesized in the cell, this “necklace” folds on itself to acquire a functional three-dimensional structure. If anything interferes with this process and impairs the completion of the folding process, the cell promptly removes and destroys the protein. A drug capable of interfering with folding can thus reduce the levels of proteins whose function can cause or promote particular diseases. Moreover, it could block proteins that are currently undruggable in their native state.
Every protein is born as a linear chain of amino acid units
The folding process is required to achieve the protein’s functional form
Druggable pockets are identified in the intermediate folding state
Small molecules can bind the pocket and block the folding process
The protein is degraded by the cellular quality control
To achieve protein degradation through PPI-FIT, one has to target the transient structures appearing during folding. Despite being temporary, such conformations last long enough to allow the binding of a small molecule. These intermediates can be thought as “pit stops” in the journey to the folded state. If we can block the protein at these stages, we can prevent the formation of the functional form of the protein.
Finding the intermediate structures is the hard part – the reliable identification of these states using standard computational approaches would take hundreds of years, even using special-purpose supercomputers. With our technology, we can overcome this sampling problem and simulate the folding pathway of large and biologically-relevant proteins.
Today we know that PPI-FIT works in the lab. Sibylla co-founders and partners have already published a proof of concept of PPI-FIT in the literature, identifying and testing candidate molecules capable of blocking the expression of the prion protein that, when misfolded, causes the Creutzfeld-Jakob disease and other lethal neurodegenerative disorders. Furthermore, Sibylla Biotech has already obtained and validated several active compounds acting on proteins of oncological interest. Sibylla’s vision promises to open new avenues to innovative drugs for a wide range of pathologies.
Spagnolli, G., Massignan, T., Astolfi, A. et al. Pharmacological inactivation of the prion protein by targeting a folding intermediate. Commun Biol 4, 62 (2021).