Total Synthesis of Malacidin A by β‐Hydroxyaspartic Acid Ligation‐Mediated Cyclization and Absolute Structure Establishment

Abstract

The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibioticresistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmocbased solid-phase peptide synthesis (SPPS) and b-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfeys analysis in our study.

Selective Peptide Cysteine Manipulation on Demand and Difficult Protein Chemical Synthesis Enabled by Controllable Acidolysis of N,S‐Benzylidene Thioacetals

“…[19,22] After treating with trifluoroacetic acid (TFA) cocktail, both NBA and NBT can be acidolyzed to produce the native peptide bond at the ligation site, albeit for NBTs much harsher conditions and longer time are required. [14] Till now both STL and CPL have been successfully applied for the chemical syntheses of various valuable peptides/proteins including immune checkpoint proteins, [23] cytokines, [24,25] nucleosome-associated proteins with PTMs, [26][27][28][29][30] antimicrobial cyclic peptides, [31][32][33][34] etc. Importantly, the generated NBA/NBT intermediate during STL/CPL becomes advantageous in challenging protein synthesis since the highly twisted structure of NBA and NBT can serve as an aggregation disruptor, which allows us to complete the first chemical synthesis of the immune checkpoint protein programmed cell death protein 1 (PD-1) extracellular domain.…”

Selective Peptide Cysteine Manipulation on Demand and Difficult Protein Chemical Synthesis Enabled by Controllable Acidolysis of N,S‐Benzylidene Thioacetals

“…[19,22] After treating with trifluoroacetic acid (TFA) cocktail, both NBA and NBT can be acidolyzed to produce the native peptide bond at the ligation site, albeit for NBTs much harsher conditions and longer time are required. [14] Till now both STL and CPL have been successfully applied for the chemical syntheses of various valuable peptides/proteins including immune checkpoint proteins, [23] cytokines, [24,25] nucleosome-associated proteins with PTMs, [26][27][28][29][30] antimicrobial cyclic peptides, [31][32][33][34] etc. Importantly, the generated NBA/NBT intermediate during STL/CPL becomes advantageous in challenging protein synthesis since the highly twisted structure of NBA and NBT can serve as an aggregation disruptor, which allows us to complete the first chemical synthesis of the immune checkpoint protein programmed cell death protein 1 (PD-1) extracellular domain.…”