Disrupting protein folding to tackle cancer

Elie Dolgin is a science journalist in Somerville, Massachusetts.

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Research at Sibylla focuses on the intermediates of protein folding.Credit: Marco Bravi Verona/Sibylla Biotech

Sibylla Biotech in Trento, Italy, spun off from the University of Trento, the National Institute for Nuclear Physics, Rome, and the University of Perugia, Italy, in 2017.

The plan to target disease-linked proteins by disrupting the folding process took a big leap forward in 2022 when the firm Sibylla Biotech in Trento, Italy, secured €23 million (US$25 million) in funding.

Sibylla — a spin-off from several Italian universities that has been longlisted for The Spinoff Prize 2023 — is pursuing a unique computational approach to drug discovery. Known as pharmacological protein inactivation by folding intermediate targeting, or PPI-FIT, the platform relies on in silico modelling to determine how a protein adopts its 3D form1.

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Armed with knowledge of that folding trajectory, scientists at the company look for transitional states that are amenable to drug binding, even when the same proteins in their fully-folded configurations are not.

"The concept is very exciting," says David Balchin, a protein-folding researcher at the Francis Crick Institute in London, who is not involved with the company. The folding trajectories predicted by Sibylla's models and lab experiments might not reflect the full complexity of protein folding in cells, Balchin cautions. "But if they are able to find drug leads like this," he says, "that would be fantastic."

Sibylla's first drug candidates centre around two proteins: KRAS and cyclin D1. Both are frequently mutated or overexpressed in tumours. And both have long been considered ‘undruggable’ targets because, in all but some rare mutated forms, the fully-folded structures lack well-defined pockets for pharmacological agents to nestle into.

Powered by Sibylla's proprietary methods, scientists led by chief technology officer Giovanni Spagnolli singled out compounds that could be directed against folding intermediates of each rogue protein.

Spagnolli helped to develop PPI-FIT as a graduate student at the University of Trento. He and his PhD advisers — biochemist Emiliano Biasini and Pietro Faccioli, a theoretical physicist now at the University of Milano-Bicocca, Italy — co-founded Sibylla along with two other Italian academics and chief executive Lidia Pieri.

Since being named a finalist for The Spinoff Prize 2021, Sibylla has produced data, as yet unpublished, showing that the compounds engage the target proteins during folding.

Part of Nature Outlook: The Spinoff Prize 2023

"That messes up the folding pathway," Spagnolli explains, prompting the degradation of the target protein through the cell's disposal system, which recognizes the improperly folded structures as aberrant and shuttles them off to be broken down. The end result is that the problematic proteins are never assembled into their cancer-causing forms.

"It sounds like magic the first time you hear it," says Ward Capoen, a partner at V-Bio Ventures, a life-sciences investment firm in Ghent, Belgium, that led Sibylla's 2022 financing round.

But as proof-of-concept examples by Sibylla's academic founders show1,2 (as well as validation work by company scientists presented at a meeting in London in March), the approach seems to be working. "Everything kept on pointing in the right direction," says Capoen, who is on the company's board of directors.

And cancer is just a starting point. "We can apply the platform to any therapeutic area," says Pieri. This includes neuroscience, which is the emphasis of a drug-discovery collaboration with the Japanese pharmaceutical firm Takeda.

Other biotech companies are developing protein-degrading drugs for some of the same disease targets. Sibylla, however, stands apart in its pursuit of folding intermediates.

The transitory nature of the intermediates can make it challenging to find drug compounds that bind to them. But once identified, says Pieri, those compounds — which Sibylla terms folding-interfering degraders — often have biochemical properties that give them an edge over other protein-degrading agents.

That idea will ultimately be put to the test when the company's anti-cancer agents enter human trials.

doi: https://doi.org/10.1038/d41586-023-01649-y

This article is part of Nature Outlook: The Spinoff Prize 2023, an editorially independent supplement produced with the financial support of third parties. About this content.

Spagnolli, G. et al. Commun. Biol. 4, 62 (2021).

Article PubMed Google Scholar

Massignan, T. et al. Preprint at https://arxiv.org/abs/2004.13493 (2020).

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