The amine capture strategy for peptide bond formation—an outline of progress

Abstract

SynopsisA review is presented of the general features of amide bond formation by prior capture of the amine-bearing peptide fragment. Capture by formation of a bond to the N-terminal nitrogen is shown in eight model systems to result in slow intramolecular acyl transfer, accompanied by anomalously large Gly/Ala and Gly/Val rate ratios. Two examples are given of rapid intramolecular acyl transfer via rings of 9 and 12 members. The transfer efficiency as estimated by the effective molarity of reactive amine at the acyl carbon in the latter case is 18M. Capture at the thiol function of an N-terminal cysteine residue is shown to be feasible in mercurithio and disulfide systems. In the latter case, effective concentrations of 3M and intramolecular transfer half-times of 10 min are demonstrated.

Chemical Synthesis of Circular Proteins

“…In the 1980s, they demonstrated its feasibility by placing both peptide segments on rigid organic templates to facilitate an O-N acyl shift in organic solvents to form a peptide bond (14). Kemp's template-based ligation approach was limited to general applications due to the use of a tricyclic organic template and the attendant slow rates of the O-N acyl shift reactions mediated by a large 12-member ring intermediate.…”

Progress in Chemical Synthesis of Peptides and Proteins

“…Third, and most seriously, many fully protected peptides have only limited solubility in organic solvents that are used for peptide synthesis. The low concentrations of reacting peptide segments often lead to slow and incomplete coupling reactions [31,32].…”

Protein chemical synthesis by serine and threonine ligation

“…In general, protein synthesis consists of two key phases: (i) solid-phase peptide synthesis (SPPS) allows for the generation of moderately sized peptide segments (up to ∼30 amino acids) (12); and (ii) chemical ligation serves to chemoselectively join these synthetic peptide fragments (13-16). In the 1970s, Kemp and coworkers conceptually devised a promising peptide ligation strategy, involving prior capture followed by acyl transfer, which has laid the foundation for the development of chemical ligation in the convergent peptide synthesis (17)(18)(19)(20)(21)(22). A milestone advance in the field was the discovery, by Kent and coworkers, of native chemical ligation (NCL) (13), in which a C-terminal peptide thioester and an N-terminal cysteine-containing peptide--both in side-chain unprotected forms--are selectively coupled to generate a natural peptidic linkage (Xaa-Cys) at the site of ligation.…”

“…In an encouraging precedent, Kemp and coworkers have examined the hemiaminal-mediated acyl transfer of 8-acetoxy-1-naphthaldehyde and 2-acetoxybenzaldehyde reacting with primary amines. Under the optimal conditions, O → N acyl transfer to the less-hindered amine (i.e., glycine and benzylamine) was observed (17,35). Subsequently, an approach involving reductive amination was developed to facilitate acyl transfer (36,37).…”