Chemical Synthesis of Six‐Atom Thioether Bridged Diaminodiacid for Solid‐Phase Synthesis of Peptide Disulfide Bond Mimics

Abstract

Solid phase peptide synthesis (SPPS) strategy based on diaminodiacids had become an effective method for the synthesis of disulfide‐containing polypeptides. At present, it remains necessary to develop a diaminodiacid with more abundant chain structures to study the structure‐activity relationship. In this work, we developed a new type of diaminodiacids containing a six‐atom thioether (C−C‐S−C‐C−C, C−C‐C−S‐C−C) bridge. The key segment protected homo‐homocystine can be efficiently obtained by converting a side chain carboxyl group into a thiol group, which contribute to the facile and efficient synthesis of new diaminodiacid. With this diaminodiacid in hand, we successfully obtained tachyplesin containing new disulfide bond mimic by solid phase peptide synthesis. The tachyplesin analog not only has similar activity as natural counterpart, but also exhibits increased stability under reducing conditions.

Recent research progress of biologically active peptides

“…Chen et al successfully obtained a fast peptide containing novel disulfide compounds through SPPS. The velocity model in the simulation not only has the activity characteristics corresponding to nature but also shows high stability under the condition of low rotation speed 90 . Okamoto et al synthesized peptide‐ N ‐acetaminoguanidine Fmoc‐SPPS by solid‐phase method.…”

“…The velocity model in the simulation not only has the activity characteristics corresponding to nature but also shows high stability under the condition of low rotation speed. 90 Okamoto et al synthesized peptide-N-acetaminoguanidine Fmoc-SPPS by solid-phase method. This method has no obvious reaction to acetaminoguanidine, and the synthesis efficiency of peptide-N-acetaminoguanidine is high.…”

A Diaminodiacid (DADA) Strategy for the Development of Disulfide Surrogate Peptides

“…Moreover, an Alloc/allyl protected diaminodiacid incorporating a six-atom (e. g. CÀ CÀ SÀ CÀ CÀ C or CÀ CÀ CÀ SÀ CÀ C) bridge (12, 13, Figure 4) has also been developed, [19] and incorporated into a six-atom thioether bridged tachyplesin mimic, which not only had the similar secondary structure and antibacterial activity as that of native tachyplesin, but also exhibited increased stability under reducing conditions. The five-atom and six-atom thioether bridged diaminodiacids, both of which were prepared with good yields, enrich the structural diversity of disulfide-containing surrogate peptides.…”