Development of Long-Acting Teriparatide Analogues through Iterative Peptide Scanning and Site-Specific Modification by Serine/Threonine Ligation

Abstract

Abstract Teriparatide, the only FDA-approved osteoanabolic drug for osteoporosis, suffers from poor metabolic stability and requires frequent subcutaneous injections, leading to suboptimal patient compliance. To find optimized teriparatide derivatives, we herein report an iterative peptide scanning strategy followed by a serine/threonine ligation (STL) chemistry for site-specific modifications. Using our 2-hydroxyphenol-pseudoproline (ψ2-hydroxyphenolpro) modification (HPM) method, two series of teriparatide analogues with different types of substituents were successfully prepared for scanning the modifiable sites and their expansibility. Through chemoselective acylation of embedded serine/threonine residues, several fatty acids of unequal lengths were introduced to further improve the pharmacokinetic properties of scanning derivatives. Among the 12 lipidated analogues, 54, 55, 62, and 63 exhibited potent antiosteoporotic activities in vitro and in vivo close to those of native teriparatide. The most effective compound, 62, also demonstrated significantly enhanced serum stability and may serve as a promising candidate for further development of long-acting antiosteoporotic pharmaceuticals.