Discovery of a potent anti-wrinkle peptide from natural origin through rational design

Summary: Abstract Body: Reducing the signs of skin aging can be achieved by targeting several biological pathways. One effective strategy is to conceal wrinkles by relaxing the underlying muscles in the dermis. At the neuromuscular endplate, the muscular nicotinic acetylcholine receptor mediates muscle contractions by facilitating the flow of sodium and potassium ions leading to depolarization of the muscle cell membrane and subsequent initiation of an action potential. While current cosmetic ingredients target the acetylcholine binding site, we discovered a series of modified peptides targeting the ion channel pore of the receptor. The molecular designs were inspired from natural toxin produced by an Egyptian insect with an aliphatic chain attached to the peptide core. We generated a combinatorial library of more than 1000 peptide designs in silico that were triaged using a three-dimensional atomistic model of the human receptor through molecular docking computations, as well as machine learning models trained with bioactivity data. The synthesizability and natural carbon origin was considered before the most promising candidates were synthesized with solid-phase peptide synthesis and evaluated in two biological assays as well as a formulation study. In total, we synthesized and biologically evaluated 134 compounds to identify our lead candidate, which shows nanomolar inhibitory activity in a patch-clamp receptor assay. In subsequent biological tests with isolated human muscle cells, we observed a highly significant reduction calcium flux in human skeletal myotubes. A formulation study with the lead candidate showed excellent stability in terms of pH, visual aspect, and odor for four months at 4°C and 40°C. In conclusion, we report the computationally supported discovery of a novel anti-wrinkle peptide of natural origin, exhibiting best-in-class biological potency through a new mode of action that can be readily formulated into cosmetic products. André Fischer¹, Remo Campiche¹, Marc Heidl¹, Eileen Jackson¹, Lise Kohler¹, Mathias Gempeler¹ 1. Beauty & Care, DSM-Firmenich AG, Kaiseraugst, AG, Switzerland. Bioinformatics, Computational Biology, and Imaging