Synthesis and modeling of natural product-inspired cyclic peptides

Cyanobacteria produce metabolites with important biological functions. Unnarmicin D, isolated from an environmental collection of <i>Trichodesmium thiebautii</i>, showed binding activity to both the μ opioid receptor (MOR) and the δ opioid receptor (DOR) while reducing pro-inflammatory cytokines in murine BV-2 microglial cells. We devised a synthetic approach replacing the fatty acid portion of unnarmicin D with a hydrophobic amino acid, which allowed for a head to tail cyclisation, with the formation of an amide bond as the final synthetic step instead of an ester. A panel of constitutional isomeric cyclized pentapeptides inspired by unnarmicin D, sharing four common amino acids, was synthesised with each synthetic step validated by ¹H NMR and HRESIMS and additional analysis. <i>In silico</i> modelling was used to assess the anti-inflammatory and analgesic potential, revealing key binding interactions with the MOR receptor and structure activity relationship between the lipophilic tail and the NOD-like receptor protein 3 (NLRP3).