Design, synthesis and evaluation of novel ring-fused heterocycles targeting bacterial and human amyloid proteins

Increased antibiotic resistance has led to significant problems with microbial biofilms in medical, environmental and industrial settings. Biofilm formation is important for microbial survival in the host and extra-host environments.

A chief determinant of surface colonization and biofilm formation is the production of an extracellular matrix (ECM) in which functional amyloid fibers have emerged as the major protein scaffold component.

We and others have shown that bacterial amyloids (e.g. curli) also affect human proteins that are prone to form amyloid associated with diseases such as Alzheimer’s and Parkinson’s.

This proposal builds on previous work (VR-NT project (2018-04589)) in which multiring-fused heterocycles were shown to affect the assembly of the bacterial amyloid curli.

Furthermore, several compounds within this collection were found to also affect human amyloids such as α-synuclein and Aβ peptide.

Synthetic methodology will be developed (e.g. photoredox catalyzed cycloadditions) to allow for late stage modifications of functionalized ring-fused heterocyles, to give novel heterocyclic central fragments of general interest to the medicinal chemistry community. These methods will allow for the design and synthesis of new, amyloid affecting compounds with higher selectivity.

Tool compounds which can assist in elucidating the exact mode of action will also be prepared. The best compounds will be studied collaboratively in advanced in vivo models.