thumbnail|right|300px|Figure 1. Classification of peptidomimetics. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as [[peptoids and β-peptides. Irrespective of the approach, the altered chemical structure is designed to advantageously adjust the molecular properties such as stability or biological activity. This can have a role in the development of drug-like compounds from existing peptides. Peptidomimetics can be prepared by cyclization of linear peptides or coupling of stable unnatural amino acids. Based on their similarity with the precursor peptide, peptidomimetics can be grouped into four classes (A – D) where A features the most and D the least similarities. Classes A and B involve peptide-like scaffolds, while classes C and D include small molecules (Figure 1).
Class A peptidomimetics
This group includes modified peptides that are mainly composed of proteogenic amino acids thereby closely resembling a natural peptide binding epitope. Usually, a small-molecular scaffold is appyled to project groups in analogy to the bioactive conformation of a peptide.
Class D peptidomimetics
These mechanistic mimetics do not directly recapitulate the side chains or conformation of a peptide but mimic its mode-of-action.
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PF-07304814_structure.png|Lufotrelvir (active form has phosphate group cleaved off)
PF-07321332.svg|Nirmatrelvir
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Uses and examples
The use of peptides as drugs has some disadvantages because of their bioavailability and biostability. Rapid degradation, poor oral availability, difficult transportation through cell membranes, nonselective receptor binding, and challenging multistep preparation are the major limitations of peptides as active pharmaceutical ingredients.
In 2004, Walensky and co-workers reported a stabilized alpha helical peptide that mimics pro-apoptotic BH3-only proteins, such as BID and BAD. This molecule was designed to stabilize the native helical structure by forming a macrocycle between side chains that are not involved in binding. This process, referred to as peptide stapling, uses non-natural amino acids to facilitate macrocyclization by ring-closing olefin metathesis. In this case, a stapled BH3 helix was identified which specifically activates the mitochondrial apoptotic pathway by antagonizing the sequestration of BH3-only proteins by anti-apoptotic proteins (e.g. Bcl-2, see also intrinsic and extrinsic inducers of the apoptosis). This molecule suppressed growth of human leukemia in a mouse xenograft model. This molecule mimics the N-terminal linear motif Ala-Val-Pro-Ile. Uniquely, the dimeric structure of this peptidomimetic led to a marked increase in activity over an analogous monomer. This binding cooperativity results from the molecule's ability to also mimic the homodimeric structure of Smac, which is functionally important for reactivating caspases. Smac mimetics of this type can sensitize an array of non-small-cell lung cancer cells to conventional chemotherapeutics (e.g. Gemcitabine, Vinorelbine) both in vitro and in mouse xenograft models.
Heterocycles are often used to mimic the amide bond of peptides. Thiazoles, for example, are found in naturally occurring peptides and used by researchers to mimic the amide bond of peptides.
See also
- Apoptosis
- Beta-peptide
- Cancer
- Clicked peptide polymer
- Depsipeptide
- Expanded genetic code
- Foldamers
- Non-proteinogenic amino acids
- Stapled Peptides