Green synthesis of bioactive oligopeptides promoted by recyclable nanocrystalline hydroxyapatite

Aim: The pharmaceutical industry is showing renewed interest in therapeutic peptides. Unfortunately, the chemical synthesis of peptides remains very expensive and problematic in terms of environmental sustainability. Hence, making peptides 'greener' has become a new front line for the expansion of peptide market. Results: We developed a mechanochemical solvent-free peptide bond-forming protocol using standard reagents and nanocrystalline hydroxyapatite as a bio-compatible, reusable inorganic base. The reaction was also conducted under ultra-mild, minimal solvent-grinding conditions, using common laboratory equipment. Conclusion: The efficacy of the described protocol was validated with the convenient preparation of endomorphin-1, H-Tyr-Pro-Trp-Phe-NH₂, the endogenous ligand of the μ-opioid receptor, currently regarded as a lead for the discovery of painkillers devoid of harmful side effects.