because they are locked into a stable -helical structure, which is the most prevalent component of protein secondary structures. Stapled peptides, a rapidly developing class of next-generation pharmaceuticals, are anticipated to combine the three-dimensionality and adaptable target identification capabilities of biologics with the synthetic manipulability and cell penetration of small molecules. The company you should use to manufacture your stapled peptide needs is CPC Scientific because it has extensively developed stapled peptide architectures. You are welcome to contact our technical consultants at any moment to discuss your demands for structural design.

The first-generation Grubbs catalyst is a relatively stable ruthenium complex utilized for olefin metathesis in peptides. It has tricyclohexylphosphine (PCy3) ligands and apical-positioned carbene carbon. The creation of a second-generation Grubbs catalyst that is more thermally stable is the result of later research (middle). A third-generation catalyst, also known as the Hoveyda-Grubbs catalyst (right), substitutes benzylidene ligands with chelating ortho-isopropoxy groups on the benzene ring for N-heterocyclic carbene ligands.

staple peptideIn order to insert hydrocarbon building blocks into peptides during olefin metathesis, Grubbs catalysts are frequently utilized. The development of macro-cyclic bridges (conformational constraint) and,-di-substitution (helix nucleation by -methylation) are two different conformational techniques that are used to generate and stabilize a -helical shape.

was created to mimic the binding domain of the human angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 in a collaboration between the Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute, New York Blood Center, and CPC Scientific. To cover the 30-amino-acid long binding domain of ACE2, a double staple motif of i + 7 and i + 4 was necessary.

Grubb’s ring-closure metathesis may result in two types of stapled peptides, i, i + 4 and i, i + 7.

High amounts of -helical content are conferred by the addition of a hydrocarbon staple, which causes:

selecting extracellular or intracellular proteins as a target

Pharmacokinetics that work and in vivo stability

Targeting of many proteins involved in diseases like cancer, diabetes, HIV, and atherosclerosis has been researched using stapled peptides. Among these proteins are:

Bcl-2-associated X protein (Bax)

Murine double minute 2 (Mdm2)

ATP-binding cassette transporter (ABCA1)

Figure 5. i, i + 4 Stapled peptide (Ac-His-S5-Ile-Leu-His-S5-Leu-Leu-Gln-Asp-Ser-NH2) bound to estrogen receptor. Stapling organizes non-adjacent leucine side chains (Leu-4 and Leu-8) project from the same side into the hydrophobic pocket of estrogen protein.[1]

The two types of stapled peptide modifications are fluorescent label and affinity tag, respectively. Fluorescein and biotin are two of the most prevalent moieties added to the N-terminus of stapled peptides, and they can be employed for biophysical characterisation and target interaction studies as well as studies of intracellular absorption. To separate the alteration from the peptide's core, a flexible molecular spacer is typically preferred.

Fluorescent labeling (FITC, 5-FAM, etc.)

Peptide stapling can also be used to reproduce other secondary protein structures, such as -sheets. In the example below, a template-assisted olefin metathesis reaction using a third-generation Hoveyda-Grubbs catalyst converts terminal olefins into internal olefins. Due to stability of the anti-parallel -sheet configuration created by the six hydrogen bonds, only one conformer is visible.[3]

References

Gothard, Chris. Unpublished work in the Nowick Group (2005).

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