Common-Precursor Protein Mimetic Approach to Rescue Aβ Aggregation-Mediated Alzheimer's Phenotypes

Abberent protein-protein interactions (aPPIs)are associatedwith an array of pathological conditions, which make them importanttherapeutic targets. The aPPIs are mediated via specific chemicalinteractions that spread over a large and hydrophobic surface. Therefore,ligands that can complement the surface topography and chemical fingerprintscould manipulate aPPIs. Oligopyridylamides (OPs) are synthetic proteinmimetics that have been shown to manipulate aPPIs. However, the previousOP library used to disrupt these aPPIs was moderate in number (& SIM;30OPs) with very limited chemical diversity. The onus is on the laboriousand time-consuming synthetic pathways with multiple chromatographysteps. We have developed a novel chromatography-free technique tosynthesize a highly diverse chemical library of OPs using a common-precursorapproach. We significantly expanded the chemical diversity of OPsusing a chromatography-free high-yielding method. To validate ournovel approach, we have synthesized an OP with identical chemicaldiversity to a pre-existing OP-based potent inhibitor of A & beta;aggregation, a process central to Alzheimer's disease (AD).The newly synthesized OP ligand (RD242) was very potent in inhibitingA & beta; aggregation and rescuing AD phenotypes in an in vivo model. Moreover, RD242 was very effective in rescuing AD phenotypesin a post-disease onset AD model. We envision that our common-precursorsynthetic approach will have tremendous potential as it is expandablefor other oligoamide scaffolds to enhance affinity for disease-relevanttargets.

Automated summary

Abberent protein-protein interactions (aPPIs) play a crucial role in pathological conditions and can be targeted for therapeutic purposes. We have developed a chromatography-free method to synthesize a highly diverse chemical library of oligopyridylamides (OPs) to enhance affinity for disease-relevant targets.