Peptide-based allosteric modulators of AMPA receptors: design, docking and ligand-receptor interactions

Neurodegenerative diseases are one of the most pressing challenges of modern medicine, a problem from which no one is immune. Many medications used to treat dementia are ineffective in eliminating the root cause of pathogenesis, or exhibit a number of side effects. Great interest has been shown in positive allosteric modulators (PAMs) of AMPA receptors and PAM-43 is one of the most promising PAMs to date. Peptide allosteric modulators are another promising area of AMPA receptor PAMs. There are numerous cases where peptide-based drugs have a gentler effect and do not cause negative side effects or addiction with prolonged use. Here we designed and synthesized two peptide structures, potential PAMs of AMPA receptors. Our studies have shown that tetrapeptide WPPW and its derivative Boc-WPPW are stable enough to bind a target receptor and do bind to it. Molecular docking of the peptides and PAM-43 revealed several specific binding sites on AMPA receptor, some of which partially overlap. These peptides notably modulate the interaction of [³H]PAM-43 at various sites of its specific binding. WPPW partially blocks [³H]PAM-43 binding at both its specific sites (high- and low-affine) in a dose-dependent manner. At certain concentrations, Boc-WPPW enhances the exposure of additional binding sites of PAM-43 that may be located not only on AMPA receptors. The peptides WPPW and Boc-WPPW may be of interest as AMPA receptor potential allosteric modulators or cofactor molecules.