The Generative Brain

PPI-FIT folding intermediate targeting anti-prion compounds (University of Trento)

This is a preclinical drug discovery line from the Dulbecco Telethon Laboratory of Prions and Amyloids at CIBIO, University of Trento, led by Emiliano Biasini. Its main idea, called PPI-FIT, is to use atom level simulations of how the prion protein (PrP) folds, find a pocket on a short lived folding intermediate, and pick small molecules that bind it so the cell destroys the protein before it matures. The 2021 paper found four such molecules; the lead, SM875, lowered PrP in several cell lines and slowed prion replication in infected cells, but was also somewhat toxic to cells. Since then the group has made more than 40 analogues, separated the two mirror image forms of SM875 and found that only one is active and that the same form carries the toxicity, and reported PrP lowering in healthy mice after injection into the spleen (conference abstract, search excerpt only). Funders are Fondazione Telethon, the CJD Foundation and an Italian PRIN grant. Earlier screens from the same lab produced other anti-prion hits. No animal efficacy or human data exist. Information only, not medical advice.

Key facts

  • PPI-FIT stands for Pharmacological Protein Inactivation by Folding Intermediate Targeting: computer simulations reconstruct the folding path of a protein, a pocket on a predicted intermediate is used for virtual screening, and binders are expected to send the protein to degradation.
  • In the 2021 Communications Biology paper about 30 virtual hits were tested and four (SM875, SM930, SM940, SM950) lowered PrP; SM875 was the strongest, with a half maximal effect near 7.9 micromolar in HEK293 cells.
  • SM875 lowered PrP protein without lowering PrP mRNA, spared two other GPI anchored proteins, acted on newly made PrP rather than mature surface PrP, and its effect was largely undone by a lysosome blocker, which the authors read as degradation through the autophagy lysosomal route.
  • In mouse fibroblasts infected with the RML prion strain, SM875 cut prion replication in a dose dependent way; at 10 micromolar the effect was comparable to the porphyrin control compound Fe3+-TMPyP.
  • Limits stated in the same paper: SM875 was toxic to cells to a varying degree, no binding to normally folded recombinant PrP was detected, and binding to the predicted pocket was not formally shown.
  • The 2021 grant from the CJD Foundation, titled Pharmacological Degraders for the Cellular Prion Protein, paid for the next step; its final report says the group improved the synthesis and built a fast cell assay, then made and tested over 40 SM875 analogues, most equal or weaker and a very few moderately better, giving a first structure activity relationship. The report calls the programme a hit to lead stage and lists brain penetration tests and then mouse models of prion disease as the steps after that.
  • A 2025 chemistry paper from the same lab with the University of Turku separated the two mirror image forms of SM875; only the (R) form lowered PrP and that same form carried the toxicity, while the (S) form did nothing.
  • A PRION 2025 conference abstract, seen only as a search excerpt, reports a focused library of SM875 analogues, direct binding of SM875 to a non native form of PrP by native mass spectrometry, and a clear drop in natural PrP levels in wild type mice given the compound into the spleen. No disease outcome is reported in the excerpt.
  • Funding history of the line: Telethon grants TCP13007 (with the Autonomous Province of Trento) and TCP14009 named in the 2021 paper and in the 2017 and 2019 screening papers, the 2021 CJD Foundation grant, an Italian PRIN 2022 grant (protocol 2022PP8WNZ) on non canonical small molecule degraders of the prion protein, and a December 2024 Telethon multi round award to improve the compounds and then test them in animal models.
  • Earlier screens from the same laboratory produced two other anti-prion hit series: compound 55 in 2017, which countered prion replication and the toxicity of mutant PrP, and four 2019 hits that move PrP off the cell surface, one of which also cut prion propagation across strains. Both carry the same Telethon grant code as the PPI-FIT work.
  • The lab runs a second, unrelated PrP lowering screen (LIPS) over more than 2,000 drugs, in which cardiac glycosides came out as strong PrP reducers, with an observational study called Brainheart approved by the local ethics committee to look for the same effect in people. No result is published.
  • Ownership: the technology is licensed to Sibylla Biotech, a 2017 spin-off of INFN and the universities of Trento and Perugia co-funded by Fondazione Telethon, which raised 23 million euro in October 2022; five authors of the 2021 paper, including the lab head, declare they co-founded and hold shares in it. The declaration says the company uses PPI-FIT across many diseases but excludes prion diseases.
  • The lab head sits on the scientific committee of the Italian fatal familial insomnia family association AFIFF.

Timeline

  1. 2015Biasini starts the Dulbecco Telethon funded prion group at the University of Trento.
  2. 2017Sibylla Biotech founded as a spin-off of INFN and the universities of Trento and Perugia, with Telethon co-funding; the lab head is a co-founder.
  3. 2017ChemMedChem paper on compound 55, a small molecule against prion replication and mutant PrP toxicity.
  4. 2019J Neurochem paper on four compounds that remove PrP from the cell surface.
  5. 2021CJD Foundation grant, Pharmacological Degraders for the Cellular Prion Protein.
  6. 2021Communications Biology paper introduces PPI-FIT and SM875.
  7. 2022Sibylla Biotech closes a 23 million euro Series A, prion diseases excluded from its PPI-FIT use.
  8. 2023Final report of the CJD Foundation grant published, over 40 analogues tested.
  9. 2024Telethon fourth multi round call results include a Trento project to improve the anti-prion compounds and test them in animal models, one of two CIBIO projects sharing 390,000 euro (sponsored university news).
  10. 2025PRION 2025 abstract reports analogue library, native mass spectrometry binding and PrP lowering in wild type mice (search excerpt).
  11. 2025Bioorganic Chemistry paper on the enantiomers of SM875 published online.
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