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The PPI-FIT (Pharmacological Protein Inactivation by Folding Intermediate Targeting) 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 a biological target -such as a protein- so to modulate or block its activity. So far, almost all drug design has focused on the native structure of the target protein. Sibylla Biotech opens the gates of 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 until it acquires a definite three-dimensional structure. If anything interferes with this process so that the protein cannot acquire its functional structure, the cell promptly removes and destroys the unfolded protein. A drug capable to interfere with folding can thus reduce or eliminate the expression of a disease-relevant protein. Moreover, it could block proteins that are currently undruggable when dealing with the native structure.

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 do this, one has not to target the native structure, but structures appearing during folding. While folding the protein can assume intermediate conformations that, while temporary, last long enough to allow the binding of a small molecule. Think of these intermediates as “pit stops” in the journey to the folded state. If we can block the protein at these stops instead of letting it arrive at the native structure, we can block the protein expression.

Finding the intermediate structures is the hard part – to do so reliably would take hundreds or even thousands of years even with specialized supercomputers. That is where another Sibylla exclusive algorithm for simulating rare protein transitions comes in handy.

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. In the first six months of operation, moreover, Sibylla Biotech has already obtained and validated in vitro potentially active compounds on proteins of oncological interest. Sibylla 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).