Peptides and Peptidomimetics: Sulfur Containing Cyclic Peptides

This set of flashcards covers the structure, function, and synthetic methods for sulfur-containing cyclic peptides, including natural examples like insulin and conotoxins, and chemical techniques like peptide stapling.

Disulfide bond

A covalent interaction ($R-S-S-R$) formed upon the oxidation of two thiols (specifically two Cys residues in a peptide) that provides stability to secondary and tertiary structures.

Insulin

A 51 amino acid peptide-based therapeutic for diabetes consisting of an A chain and B chain linked by 3 disulfide bonds (2 inter-chain and 1 intra-chain).

Connecting peptide

A segment in the nature-synthesized linear precursor of insulin that holds the peptide in the correct conformation before being cut out to yield active insulin.

Cyclotides

Plant-derived macrocyclic peptides featuring a cyclic cystine knot (CCK) formed by six cysteine residues on a head-to-tail cyclic backbone.

Chlorotoxin

A 36-amino acid peptide from deathstalker scorpion venom with 8 cysteine residues and 4 disulfides that acts as a competitive inhibitor of chloride ion channels.

Conotoxins

Peptides found in cone snail venom that typically have 2-3 disulfide bonds and can contain defined secondary structural motifs like alpha helices or beta sheets.

Oxidation of free thiols

A synthetic method for disulfide formation often performed at high dilution using oxidants such as air (generating $H_2O_2$), DMSO, or Glutathione.

I2 (Iodine)

A reagent used for the oxidation of protected thiols that can have cross-reactivity issues with electron-rich aromatic amino acids like Tyr, Trp, and Methionine.

Diphenyl sulfoxide + Methyltrichlorosilane

A specific reagent combination used for forming disulfides from protected thiols, such as those protected by Acm or Trt groups.

Directed nucleophilic displacement

A disulfide formation approach often applied to intermolecular bonds using leaving groups (LG) such as 2-pyridinylsulfenyl (S-Pyr) or 2-nitrophenylsulfenyl (S-Nps).

DTT (Dithiothreitol)

A smelly thiol-containing reducing agent used to chemically cleave disulfide bonds.

TCEP (Tris(2-carboxyethyl)phosphine)

An odorless, air-stable phosphine reagent that is highly reactive and specific towards the reduction of disulfide bonds.

Selenocysteine (Sec, U)

A selenium-containing amino acid ($HSe-CH_2-CH(NH_2)-COOH$) found in nature that can form diselenide bonds which are more stable and form faster than disulfides.

Peptide stapling

A technique in peptide chemistry used to mimic disulfide bonds with more stable alternatives like carbon analogs (carba-analogs) to improve serum stability.

Carba-Oxytocin

A mimic of the peptide Oxytocin that replaces the disulfide bond with a carbon-based bridge, resulting in improved serum stability but lower biological activity ($EC_{50}$ of $38\,ng/mL$ vs $2.7\,ng/mL$).