Efforts Towards Enhancing the Proteolytic Stability of Peptide Hormone to Combat Osteoporosis

Abstract

Osteoporosis is a chronic skeletal condition marked by a gradual loss of bone density and the breakdown of bone microstructure, which significantly elevates the risk of fractures in the spine, hip, and wrist. This condition represents a major global health challenge, particularly affecting postmenopausal women and the elderly population. Among the available therapeutic strategies, parathyroid hormone (PTH) peptide analogues represent a unique and effective anabolic approach to osteoporosis treatment. Agents such as teriparatide and abaloparatide play a significant role in the management of severe osteoporosis. Unlike antiresorptive drugs, PTH analogues stimulate new bone formation by activating osteoblasts. This bone-building mechanism offers a distinct therapeutic advantage by promoting bone regeneration rather than merely slowing bone loss. However, the widespread clinical application of PTH analogues is constrained by the high cost of peptide synthesis and their short in vivo half-life, which necessitates frequent administration. Given that osteoporosis disproportionately affects the ageing population, we aim to enhance the proteolytic stability of abaloparatide through site-specific PEGylation and the incorporation of non ribosomal amino acids. We also aim to develop cost-effective strategies to improve peptide yield and purity using dipeptide-based coupling approaches.