Chemoselective modular constructions of peptides and cyclic peptides functional architectures

Abstract

During the past decade, peptide-based therapeutics have become one of the hot spots in drug development due to their high selectivity, tolerability and customizability. In particular, cyclic peptides that are restrained in their bioactive states have been reported with better biological activities compared to their linear counterparts, such as higher binding affinity and improved stability towards protease degradation. The development of novel strategies to construct cyclic peptides and hybrid peptide/cyclic peptide structures for biological and pharmaceutical studies is of great importance. In this thesis, three methodological studies for the construction of cyclic peptide related architectures, peptide-peptide/drug conjugates, and novel cyclic peptide one-bead-one-compound (OBOC) libraries were presented respectively. For the first project, a facile synthetic strategy has been developed for constructing diverse peptide structural architectures via chemoselective peptide ligation. The major advancement is the utilization of benzofuran moiety as the peptide salicylaldehyde ester surrogate and Dap–Ser/Lys–Ser dipeptide as the hydroxyl amino functionality. These reaction counterparts have been successfully installed on the side chain to diversify the motifs constructed. Side chain-to-side chain cyclic peptides, branched/bridged peptides, tailed cyclic peptides and multi-cyclic peptides have been devised and synthesized by this strategy. Overall, this versatile method has offered an easy access to a diverse class of peptide structural motifs. For the second project, the guanidine additive enabled intermolecular ortho-phthalaldehyde (OPA)-amine-thiol three-component reactions has been developed for modular constructions. The key is to employ guanidine as an effective additive to suppress the competing two-component reactions pathway. With this strategy, peptide-peptide and peptide-drug conjugates have been prepared in one step, with excellent conversions and isolated yields. In addition, a further functionalized conjugate has been synthesized by utilizing the pre-modified OPA moiety. We believe this strategy will serve as a powerful tool for constructing conjugates in a modular manner. For the last project, we have established a general method to construct the novel OPA-cyclic peptide OBOC library. The major advancement is the utilization of lysine and penicillamine (3°-thiol) as reacting counterparts to afford cyclic peptides that are stable over a wide pH range under room temperature and air atmosphere. Moreover, a spatial segregation approach has been adopted to incorporate the corresponding linear peptide for sequence decoding. A random OPA-cyclic peptide OBOC library has been constructed and is ready for biological screening.