Strategies for Fine-Tuning the Conformations of Cyclic Peptides

Jwad, Rasha Saad; Weissberger, Daniel; Hunter, Luke

doi:10.1021/acs.chemrev.0c00013

Cited by 98 publications

(85 citation statements)

References 407 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Dunitz-Wase concept predicts two stable confirmations of cyclic hexapeptides, which reassemble the chair and boat conformations of cyclohexane. [17] 2 d). Importantly, the crystal of (4 c) 2 also contains one potassium cation per two molecules of (4 c) 2 .…”

Section: Resultsmentioning

confidence: 98%

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

et al. 2021

View full text Add to dashboard Cite

Autocatalytic reaction networks are instrumental for validating scenarios for the emergence of life on Earth and for synthesizing life de novo. Here, we demonstrate that dimeric thioesters of tripeptides with the general structure (Cys-Xxx-Gly-SEt) 2 form strongly interconnected autocatalytic reaction networks that predominantly generate macrocyclic peptides up to 69 amino acids long. Some macrocycles of 6-12 amino acids were isolated from the product pool and were characterized by NMR spectroscopy and single-crystal X-ray analysis. We studied the autocatalytic formation of macrocycles in a flow reactor in the presence of acrylamide, whose conjugate addition to thiols served as a model "removal" reaction. These results indicate that even not template-assisted autocatalytic production combined with competing removal of molecular species in an open compartment could be a feasible route for selecting functional molecules during the pre-Darwinian stages of molecular evolution.

show abstract

Section: Resultsmentioning

confidence: 98%

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The molecular structures of ( 1 c ) 2 and ( 4 c ) 2 , obtained from X‐ray analysis, are shown in Figure 2 a,c. The Dunitz‐Wase concept predicts two stable confirmations of cyclic hexapeptides, which reassemble the chair and boat conformations of cyclohexane [17] . ( 1 c ) 2 takes the chair conformation, which is stabilized by an intramolecular hydrogen bond (O⋅⋅⋅N 2.958 Å) (Figure 2 a).…”

Section: Resultsmentioning

confidence: 99%

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

et al. 2021

View full text Add to dashboard Cite

Autocatalytic reaction networks are instrumental for validating scenarios for the emergence of life on Earth and for synthesizing life de novo. Here, we demonstrate that dimeric thioesters of tripeptides with the general structure (Cys‐Xxx‐Gly‐SEt)2 form strongly interconnected autocatalytic reaction networks that predominantly generate macrocyclic peptides up to 69 amino acids long. Some macrocycles of 6–12 amino acids were isolated from the product pool and were characterized by NMR spectroscopy and single‐crystal X‐ray analysis. We studied the autocatalytic formation of macrocycles in a flow reactor in the presence of acrylamide, whose conjugate addition to thiols served as a model “removal” reaction. These results indicate that even not template‐assisted autocatalytic production combined with competing removal of molecular species in an open compartment could be a feasible route for selecting functional molecules during the pre‐Darwinian stages of molecular evolution.

show abstract

“…Peptide cyclization, backbone N‐methylation, and the use of d and non‐proteinogenic amino acids are common strategies in medicinal chemistry to enhance the metabolic stability, cell permeability, and bioavailability of synthetic peptides [1–6] . Methylation is a particularly desirable modification since it reduces the polarity of the amide bond, introduces conformational constraints and sequential introduction appears additive in terms of increasing membrane permeability [6–8] .…”

Section: Figurementioning

confidence: 99%

Engineering of a Peptide α‐N‐Methyltransferase to Methylate Non‐Proteinogenic Amino Acids

et al. 2021

View full text Add to dashboard Cite

Introduction of α‐N‐methylated non‐proteinogenic amino acids into peptides can improve their biological activities, membrane permeability and proteolytic stability. This is commonly achieved, in nature and in the lab, by assembling pre‐methylated amino acids. The more appealing route of methylating amide bonds is challenging. Biology has evolved an α‐N‐automethylating enzyme, OphMA, which acts on the amide bonds of peptides fused to its C‐terminus. Due to the ribosomal biosynthesis of its substrate, the activity of this enzyme towards peptides with non‐proteinogenic amino acids has not been addressed. An engineered OphMA, intein‐mediated protein ligation and solid‐phase peptide synthesis have allowed us to demonstrate the methylation of amide bonds in the context of non‐natural amides. This approach may have application in the biotechnological production of therapeutic peptides.

show abstract

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

Cited by 98 publications

References 407 publications

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

Kinetic Selection in the Out‐of‐Equilibrium Autocatalytic Reaction Networks that Produce Macrocyclic Peptides

Engineering of a Peptide α‐N‐Methyltransferase to Methylate Non‐Proteinogenic Amino Acids

Contact Info

Product

Resources

About