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

Abstract

Disulfide bond‐containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid‐phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA‐based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA‐based disulfide surrogates are described.

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

“…[71][72][73][74][75][76][77][78][79] They have found increasing applications in the synthesis of various proteins and peptides, including posttranslationally modified proteins, customdesigned proteins, protein-based probes, membrane proteins, and cyclic peptides etc. [80][81][82][83][84] Different from the linear synthetic strategy developed by the Payne group, the Li group achieved the first convergent total synthesis of teixobactin through Ser ligation mediated "6 + 5" strategy (Figure 13). 67,85 Generally, the linear hexapeptide (1-6) 39…”

DIC/Oxyma‐based accelerated synthesis and oxidative folding studies of centipede toxin RhTx

“…Although the one-step oxidative folding is convenient and only once RP-HPLC was required for purification, there is the possibility of disulfide bond misfolding. 47,48 In order to guarantee the correct folding of disulfide bonds, linear peptides 2, 3, and 4 were refolded by the twostep oxidative folding strategy, affording the peptides 12, 14, and 16, respectively (Figure 3 and Table S2). The K 3 [Fe (CN 6 )] solution was used for the construction of the first disulfide bond.…”

Use of a Removable Backbone Modification Strategy to Prevent Aspartimide Formation in the Synthesis of Asp Lactam Cyclic Peptides†

“…Lactam cyclic peptides have attracted widespread attention recently due to their structural rigidity, metabolic stability, and interesting biological activity; [ 1‐7 ] and the Asp‐based lactam cyclic peptide drug bremelanotide (Scheme 1), a highly potent synthetic analogue of α‐melanocyte‐stimulating hormone, was recently approved by FDA. [ 8 ] Asp‐based lactam cyclic peptides are usually synthesized by Fmoc solid‐phase synthesis (SPPS), [ 9‐15 ] which generally entails removal of the temporary protecting groups on the side chains of Asp and Lys (or their derivatives) prior to on‐resin Asp‐Lys lactam cyclization.…”