Accelerating chemoselective peptide bond formation using bis(2-selenylethyl)amido peptide selenoester surrogates

Abstract

SeEA latent selenoester: go fast by switching to selenium.

A simple and traceless solid phase method simplifies the assembly of large peptides and the access to challenging proteins

“… 14 , 25 These bifunctional peptides were produced by two different methods, as shown in Scheme 3 . 13 , 16 Succinimidyl acetoacetate (AcA-OSu, commercially available) can be used for modifying the peptidyl resin after Fmoc-SPPS, starting from SEA PS resin 1 ( Scheme 3A , method A). The peptide cleavage and deprotection in TFA is carried out in the absence of triisopropylsilane (TIS), and any standard thiol scavenger is replaced by 3,4-difluorothiophenol to preserve the AcA moiety from degradation during this step.…”

“…In recent years, there has been keen interest in simplifying protein assembly while minimizing isolation and purification steps. A dynamic area of research is the conception of one-pot peptide segment assembly schemes, which rely on the development of novel Cys protection strategies, 5 – 13 latent thioester or selenoester surrogates, 14 – 16 or kinetically controlled ligation methods 17 – 21 (and combinations thereof). An alternative approach is to perform stepwise assembly of peptide segments on a water-compatible solid support.…”

One‐Pot Four‐Segment Ligation Using Seleno‐ and Thioesters: Synthesis of Superoxide Dismutase

“…By using the difference in the reactivity of the selenoester and thioester surrogates, Melnyk et al. recently realized the one‐pot ligation of three segments . In contrast to these successful achievements, the selenoester has seldom been used as an acyl donor in the direct aminolysis reaction for forming a peptide bond, although it was developed a fairly long time ago …”

Building Peptide Bonds in Haifa: The Seventh Chemical Protein Synthesis (CPS) Meeting

“…Many innovative adaptations of NCL, such as small molecules that facilitate ligation as well as techniques that go beyond the classical Cys‐based NCL were a major focus of the seventh CPS. Oleg Melnyk (CNRS, University of Lille, France) presented recent developments by his lab in the synthesis of bis(2‐sulfanylethyl)amido (SEA) and bis(2‐selenylethyl)amido (SeEA) latent thioester and selenoester surrogates that enable efficient one‐pot peptide assembly. This was demonstrated by the total synthesis of a biologically active NK1 protein, a natural hepatocyte growth factor variant consisting of 180 amino acids.…”

“…The challenges lie in straightforward synthetic methods forp roducing the individual peptide segments as well as in the design of efficient and robust processes for the assembly of peptides egmentsi nw ater.M any innovative adaptations of NCL, such as small molecules that facilitatel igation as well as techniques that go beyond the classical Cysbased NCL were am ajor focus of the seventh CPS. Oleg Melnyk (CNRS, Universityo fL ille, France) presented recent developmentsb yh is lab in the synthesis of bis(2-sulfanylethyl)amido (SEA) [1] and bis(2-selenylethyl)amido (SeEA) [2] latent thioester and selenoester surrogates that enable efficient one-pot peptidea ssembly.T his was demonstrated by the total synthesis of ab iologically active NK1 protein, an aturalh epatocyte growth factor variant consisting of 180 amino acids. Lei Liu (TsinghuaU niversity,C hina) described an alternative strategy of using peptideh ydrazides as "thioester synthons"i np eptide ligation.…”