Designing peptide inhibitors targeting LRP6 co-receptor to restrict its association to DKK1; an Alzheimer’s disease therapeutic strategy

We aimed to design and develop short peptide inhibitors targeting Low-Density Lipoprotein receptor-related Protein 6 (LRP6) as a therapeutic for Alzheimer’s disease (AD). Considering the critical association of LRP6 co-receptor with Dickkopf-related protein 1 (DKK1), which is majorly involved in the upregulation of AD via canonical Wnt signaling. After assessing the critical amino acid residue involved in the DKK1-LRP6 complex, a 16-amino acid (16aa) length short peptide was retrieved to be used as the inhibitory peptide. Further, using alanine scanning, we generated 16 different mutated peptides and their binding potential in-silico to LRP6, which ensured the blockage of the DKK1 association to LRP6. Further, the peptides were subjected to envisage their toxicity, physicochemical properties, and ADMET properties. In the results, apart from the native inhibitory peptide (16aa), the mutated peptides 16aa8, 16aa1, 16aa7, and 16aa6 showed good binding with LRP6 which made the blockage of DKK1 association to LRP6. As a future perspective, the top-scored peptides including the native peptides will be screened for synthesizing characterizing, and validating their in vitro and in vivo therapeutic potential to treat AD through the DKK1 inhibition mechanism.