PPI-FIT: A paradigm shift in drug discovery
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 -aminoacids- linked each to the next like the pearls in a necklace. When synthetized 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 mature 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 functional protein. Moreover, it could block proteins that are currently undruggable when dealing with the native structure.
To do this, one has to target not 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 to 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 algorithms for simulating rare protein transitions comes in handy.
Today we know that PPI-FIT works in the lab. Sibylla co-founders and partners 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.
References: Spagnolli, G. et al. Pharmacological protein inactivation by targeting folding intermediates. 31 March 2020. bioRxiv 2020.03.31.018069; doi: 10.1101/2020.03.31.018069
A Quantum Leap in Molecular Simulations
Sibylla innovative approach to drug design requires to know in atomic detail the structure of protein folding intermediates. This is a hard problem. While the native structure of a protein is usually relatively static, and can be reconstructed experimentally (or deduced theoretically with varying degrees of accuracy), folding is a dynamical process. A folding protein explores a staggering number of different three dimensional configurations across a complex energy landscape. Despite the ongoing increase in computing power and even the building of supercomputers specialized, at the hardware level, to perform structural dynamics calculations, reliably finding structures of folding intermediates would require in most cases hundreds if not thousands of years of calculations.
This is where another technological asset in exclusive license to Sibylla Biotech come to rescue: a range of innovative algorithms which exploit a powerful mathematical method called functional integration. In particular, these algorithms are inspired by the so-called Instanton Theory, a mathematical method originally conceived within theoretical physics to describe quantum mechanical phenomena in the sub-atomic world. The founding scientists of Sibylla have successfully repurposed this framework and used it to obtain powerful algorithms that are capable to overcome computational limitations in the folding pathway problem. This way, Sibylla’s own computer cluster can accelerate the relevant calculations tens of thousands of times, yielding an atomic-level picture of the folding of the protein of interest in a few weeks. From this, the intermediate structures can be extracted and analyzed for the presence of promising binding pockets, on which then candidate molecules can be screened first digitally and then experimentally.
References: Ianeselli, A. et al. Atomic detail of protein folding revealed by an ab initio reappraisal of circular dichroism. 23 Feb 2018. Journal of the American Chemical Society. doi: 10.1021/jacs.7b12399