The ocean as a source of new anti-inflammatory and anti-pruritic molecules

Abstract

Background: Pruritus, the most common symptom of skin diseases, is considered a chronic condition when experienced for more than six weeks. Although the etiology of the symptom remains elusive, chronic pruritus has been associated with neurokinin 1 receptor (NK1R) and its agonist substance P [1]. Since pruritus and inflammation often go together, the development of compounds with dual activity, specifically anti-inflammatory and anti-pruritic, is an upcoming strategy [1,2]. Objective: The present work aimed the discovery of new molecules inspired in models from the sea, a source of unique chemical structures with anti-pruritic and anti-inflammatory activities. Methods: Seventy marine-inspired compounds were tested in silico regarding their binding affinity to NK1R and their pharmacokinetic properties evaluated using SwissADME software. In vitro molecules’ cytotoxicity was evaluated in cells representative of the skin constitution, namely keratinocytes (HaCaT), macrophages (Raw 264.7), and fibroblasts (3T3). The anti-inflammatory properties were investigated in macrophages, by evaluating nitric oxide synthase (iNOS) protein levels (Western blot analysis), nitric oxide (NO) production (Griess assay) and NO scavenging potential using an in chimico assay. Results: The tested compounds demonstrated a high binding affinity for NK1R in silico and no relevant cytotoxicity in vitro. Some compounds were able to reduce inflammation through the decrease of the pro-inflammatory mediator NO, not because of their NO scavenging potential, but by decreasing iNOS protein levels, thus suggesting the blockade of pro-inflammatory signaling pathways upstream iNOS synthesis, namely the transcription factor NF-kB. Importantly, most tested marine-inspired compounds presented MW up to 500 and log P in the range 2.40-5.76 which favours good skin permeation. Conclusions: The ocean is a potential source of anti-inflammatory compounds and NK1R antagonists for the treatment of skin conditions associated with pruritus and inflame mation.