Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disorder proven to be caused by the aggregation of protein tau into fibrils, resulting in neuronal death. The irreparable neuronal damage leads to irreversible symptoms with no cure; therefore, disaggregation of these tau fibrils could be targeted as a therapeutic approach to AD. Here we have developed a fungal natural product library to screen for secondary metabolites that have bioactive potential towards AD tau. Our initial screenings indicate that penicillic acid demonstrates anti-aggregation activity towards tau, while further in vitro experiments reveal that penicillic acid directly inhibits tau by disaggregating fibrils. Although penicillic acid possesses blood-brain barrier penetrability properties that are computationally predicted to be favorable, it is presumed to contain some mutagenic effects as well. To address this, we used the backbone of penicillic acid as a chemical probe to discover similar compounds that can inhibit AD tau aggregation with limited mutagenicity. This work suggests the potential of discovering chemical probes through natural product screening for small-molecule drug discovery of tauopathies.