Design and Validation of Novel Potential Antiperspirant Peptides Blocking M3-Gαq Sweat Signaling Cascade

Sweat production is vital for human survival as its evaporation eases heat dissipation. Nevertheless, excessive perspiration or hyperhidrosis causes stress and discomfort affecting people’s quality of life. Persistent hyperhidrosis treatments during long time periods with classical antiperspirants, anticholinergic medications or botulinum toxin injections produce diverse side effects that limit their clinical use. Inspired in anticholinergic compounds, we used an in silico molecular modelling approach to design novel peptides targeting sweat induction signaling cascade initiated by M3 activation and coupling to Gq- αβγ in order to treat hyperhidrosis conditions. We selected 8 designed peptides that inhibited acetylcholine-induced M3 activation in CHO cells. The most potent peptides were lipopeptides including palmitoyl and myristoyl groups pLI1-3, pLI1-3-n6.1, pLI1-3-n6.2 and mLI2-1 as corroborated by their IC₅₀ value. Noteworthy, local acute and chronic administration of the most potent pLI1-3 peptide significantly decreased pilocarpine-induced sweating in an in vivo rat model. Taken together, our in silico approximation produced active peptides able to attenuate excessive sweating by halting M3 activation-induced sweat production signaling cascade, and proposed pLI1-3 peptide as a potential new anti-hyperhidrosis candidate for clinical development.