Investigation on side-product formation during the synthesis of a lactoferrin-derived lactam-bridged cyclic peptide

Bovine lactoferrin C-lobe is able to prevent both influenza virus hemagglutination and cell infection. In particular, it was demonstrated that the fragment 418SKHSSLDCVLRP429 is a potent antiviral peptide. Therefore, we tried to increase the stability of this fragment through side-chain lactam cyclization of the peptide, S[KHSSLD]CVLRP (1). However, classic strategy involving solid-supported cyclization of the linear precursor, containing orthogonal allyl/alloc-based protection for the key amino and carboxyl residues, did not provide the desired cyclic peptide. Here, we report the identification of problematic stretches during the sequence assembly process and the optimization of the different parameters involved in the construction of 1. Results indicated a significant influence of β-protecting group of both aspartic acid and adjacent cysteine residues on the formation of side products. Therefore, the identification of suitable β-protecting groups of these residues allowed us to optimize the synthesis of designed lactam-bridged cyclic peptide.