Project number 14

Design of functional amyloid peptides that kill drug resistant fungal pathogens

Amyloid structure is protein assembly state associated to protein misfolding and aggregation in a range of human degenerative conditions, such as cataract, Alzheimers and type II diabetes. Intruigingly amyloid structure is also used by nature for a variety of functions, including silk fibre in spider or hormone storage, UV protection or blood clotting in human. We recently developed a novel technology that aims to design functional amyloid peptides that knock down protein function in a specific manner by inducing amyloid conversion. We demonstrated proof of this concept by making novel antibiotics (Bednarska et al, Mol Microb 2015) and anti-tumorals (Gallardo et al, Science, 2016). Here we want to set out to develop novel antifungal compounds as there is a steady increase in the number of fungal infections. The most common human fungal pathogens is Candida albicans, but others, such as C. glabrata and C. Parapsilosis, are on the rise. The reason for this is the increase in the immunocompromized population, including the elderly, the advancement of medical care, including the use of various implants that are ideal substrates for the very difficult to treat biofilms and a rapid increase in resistance by these pathogens to the currently used antifungal drugs.
We aim to develop aggregating peptides (called PeptInsTM) that will induce the aggregation of fungal proteins, which have a perfect match with these peptides. The sequence of the peptide is identified using proprietary software algorithms that predict which part of a primary protein sequence is prone to start cross beta aggregation. We have preliminary data with a number of different targets in Candida albicans and Candida glabrata that show that the technology works. For one of the targets, calcineurin, we have promising data that our technology targets specifically the fungal protein but not the human, which shows a few amino acid differences in the peptide sequence. The aim is to further develop this novel therapeutic approach and to understand the underlying molecular mechanisms of this induced protein aggregation. The current project involves microbiology, molecular biology, molecular biophysics, cell biology and bioinformatics.
The lab of Prof. Van Dijck has strong expertise on human fungal pathogens with a main focus on Candida albicans. Prof Joost Schymkowitz & Prof Frederic Rousseau (VIB, KUL) are experts in protein aggregation, and are the inventors of the Targeted Protein Aggregation Technology which will be used in this project to develop novel antifungals.

Keywords
amyloid aggregation, Candida sp., antifungal peptides

Supervisors
Patrick Van Dijck, VIB Dept. of Molecular Microbiology, KU Leuven, Leuven
Joost Schymkowitz/Frederic Rousseau, VIB SWITCH Lab, KU Leuven, Leuven