A disulfide bond replacement strategy enables the efficient design of artificial therapeutic peptides

• Published in: Tetrahedron Vol. 70; no. 42; pp. 7774 - 7779
• Main Authors: Aoki, Kazuhiro, Maeda, Miki, Nakae, Takashi, Okada, Yohei, Ohya, Keiichi, Chiba, Kazuhiro
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 21.10.2014; Elsevier
• Subjects: Amine cross-linkages; Bone resorption-blocking activities; Chemistry; Chemistry, Organic; Disulfide bonds; Hydrophobic tags; Physical Sciences; Science & Technology; Therapeutic peptides; Bone resorption-blocking activities; Disulfide bonds; Therapeutic peptides; Hydrophobic tags; Amine cross-linkages; PHASE SYNTHESIS; IMI; ANALOGS; BIOLOGICAL-ACTIVITIES; CYSTINE; POTENT; ALPHA-CONOTOXIN; OXYTOCIN; CYCLIZATION
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2014.05.079

We demonstrate that disulfide bond replacement is an efficient strategy for engineering therapeutic peptides. In previous work, short peptide fragments, known as WP9QY, with sequence homology with the predicted ligand contact surface of the receptor activator of NF-κB (RANK) were crosslinked through intramolecular disulfide bonds to inhibit RANK ligand (RANKL)-induced signaling, osteoclastogenesis, bone resorption in vitro, and bone loss in vivo. We report that replacement of the disulfide bond of WP9QY with an amine cross-linkage results in a significant improvement in enzymatic stability, with only a slight loss of bone resorption-blocking activity in vitro. Furthermore, the WP9QY derivative inhibits bone loss significantly in vivo, whereas the native form of WP9QY was not effective under the same conditions. [Display omitted]