Toward Semisynthetic Lipoproteins by Convergent Strategies Based on Click and Ligation Chemistry (original) (raw)

The use of a cysteinyl prolyl ester (CPE) autoactivating unit in peptide ligation reactions

Tetrahedron, 2009

A peptide containing a cysteinyl prolyl ester (CPE) moiety at the C-terminus (CPE peptide) is spontaneously transformed into a diketopiperazine thioester via an intramolecular N-S acyl shift reaction, followed by diketopiperazine formation. The CPE peptide can be ligated with a Cys-peptide in a one-pot procedure. The peptide diketopiperazine thioester can also be transformed into a peptide thioester by intermolecular thiol-thioester exchange with external thiol compounds such as sodium mercaptoethanesulfonate. Since CPE peptides can be prepared by standard Fmoc solid-phase synthesis, it is a versatile alternative to the peptide thioester, providing a flexible ligation strategy that promises to be useful in polypeptide synthesis.

Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis

Nature Communications, 2021

Nonribosomal peptide synthetases containing starter condensation domains direct the biosynthesis of nonribosomal lipopeptides, which generally exhibit wide bioactivities. The acyl chain has strong impacts on bioactivity and toxicity, but the lack of an in-depth understanding of starter condensation domain-mediated lipoinitiation limits the bioengineering of NRPSs to obtain novel derivatives with desired acyl chains. Here, we show that the acyl chains of the lipopeptides rhizomide, holrhizin, and glidobactin were modified by engineering the starter condensation domain, suggesting a workable approach to change the acyl chain. Based on the structure of the mutated starter condensation domain of rhizomide biosynthetic enzyme RzmA in complex with octanoyl-CoA and related point mutation experiments, we identify a set of residues responsible for the selectivity of substrate acyl chains and extend the acyl chains from acetyl to palmitoyl. Furthermore, we illustrate three possible conformati...

Applications of Chemical Ligation in Peptide Synthesis via Acyl Transfer

Topics in current chemistry, 2015

The utility of native chemical ligation (NCL) in the solution or solid phase synthesis of peptides, cyclic peptides, glycopeptides, and neoglycoconjugates is reviewed. In addition, the mechanistic details of inter- or intra-molecular NCLs are discussed from experimental and computational points of view.

Synthesis of Glyco(lipo)peptides by Liposome-Mediated Native Chemical Ligation

Organic Letters, 2006

Although native chemical ligation (NCL) is emerging as a powerful method for the assembly of (glyco)peptide building blocks, its applicability is reduced when peptide segments are poorly soluble in aqueous buffer. We have found that incorporating reactants in liposomes allows NCL of lipophilic peptides and lipopeptides. Furthermore, the reaction rates of liposome-mediated NCL are higher than traditional reaction conditions resulting in improved yields. Recently, we demonstrated 1 that the three-component vaccine candidate 1 (Figure 1) composed of the tumor-associated Tn antigen, 2-4 the peptide T-epitope YAFKYARHANVGRN-AFELFL (YAF), 5 and the lipopeptide S-[(R)-2,3-dipalmi-toyloxy-propyl]-N-palmitoyl-(R)-cysteine (Pam 3 Cys) 6,7 can elicit IgG antibody responses. This finding was significant because it had been difficult to elicit relevant immune responses against tumor-associated carbohydrates. 8,9 To optimize the immunological properties of a threecomponent vaccine, a synthetic methodology was required, which would allow a convenient assembly of a number of Band T-epitopes and lipopeptide adjuvants into a range of vaccine candidates. During our investigation, we discovered that liposome-mediated native chemical ligation (NCL) is a