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Global and local restrictions Peptidomimetics

Global and local restrictions Peptidomimetics

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Global and local restrictions Peptidomimetics

  1. 1. What is peptidomimetics? • small protein-like chain designed to mimic a peptide. •Arise either from modification of an existing peptide, or by designing similar systems that mimic peptides •Eg: peptoids and β-peptides. • these are molecules with significantly reduced peptide character that mimic the bioactive conformation of peptides, and thus retain the ability to interact with the biological target and cause the same biological effect  Peptidomimetics- incorporating conformational constraints locally or globally
  2. 2. Why peptidomimetics are needed? • By altering chemical structure is designed to advantageously adjust the molecular properties such as, stability or biological activity. •have a role in the development of drug-like compounds from existing peptides •altered backbones and the incorporation of nonnatural amino acids. •It utilized to design small molecules that selectively kill cancer cells, an approach known as targeted chemotherapy, by inducing programmed cell death by a process called apoptosis.
  3. 3. • Peptide derivatives that contain conformationally restricting amino acid units or other conformational constraints called conformationally constrained (or restricted)peptide analogs. What are conformational constraints? •Conformational restriction is a very powerful method for probing the bioactive conformations of peptides.
  4. 4. • Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. Fig.Backbone and side chain torsional angles •For example, a simple tripeptide such as thyrotropin-releasing hormone with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous.
  5. 5.  Method needed to exclude potential conformers. • Modern biophysical methods e.g., X-ray crystallography or isotope edited nuclear magnetic resonance • (NMR) can be used to characterize peptide- protein interactions for soluble proteins. thyrotropin-releasing hormone
  6. 6.  Methods for restricting- conformations •peptide backbone cyclization •disulfide bond formation •side-chain cyclization, •and metal ion chelation.  Cyclization is one of the earliest techniques applied to design peptidomimetics. • Cyclic peptides are more stable to amide bond hydrolysis and allow less conformational flexibility
  7. 7. Methodologies for design peptides Two main methods are used:- I.local constraints and II. Global constraints • for reducing the number of the accessible conformations and rendering the selectivity of synthetic peptides more stringent than that afford by the sequence could take advantage by introduction of two main constraints in to peptide
  8. 8. Global restrictions  simplest way to introduce a conformational constraint into a peptide sequence is by cyclization.  increases the in vivo stability of the cyclic peptides compaired to linar one.  Cyclization can be obtained by: • connecting the N- with the C-terminus (head-to-tail) portion of the peptide sequence. or • Couple of either the N- or the C-terminus with one of the side chains (backbone-to-side chain) • or the couple of side chains not involved in specific interactions with other (side chain-to-side chain).
  9. 9. Local restrictions • The simplest local constraints in which introducing the substitution of a methyl group for a hydrogen adjacent to a rotable bond. • For example, replacing the α -hydrogen on alanine with a methyl group gives α - aminoisobutyric acid (Aib). This residue was found in peptide sequences from a fungal source. α - aminoisobutyric acid
  10. 10. • The steric bulk of the methyl group reduced the rotational freedom of the two peptide backbone angles Ψ and Ф. • In the case of Aib, the allowable Ф and Ψ backbone angles in peptides are restricted to values near –57°, -47° and +57°, +47°. • The introduction of an alkyl group either at the β- position or on aromatic ring of naturally occurring amino acids rigidifies the conformational flexibility of the side chain.
  11. 11. • Three of natural amino acids show β -disubstitutions: • Valine (two methyl groups) • Isoleucine (a methyl and an ethyl) and • Threonine (a methyl and a hydroxyl). Additionally, β-substitution leads to a second asymmetric center in the amino acid structure.
  12. 12. • It allowing the peptide backbone and the side chain some degree flexibility • Another advantage of these modifications is that the extra alkyl groups can enhance the lipophilicity of peptide, and therefore can help it to overcome membrane barrier • the introduction of a covalent bond between the aromatic ring of an α -amino acid residue and the peptide backbone has proven to be a useful further conformation restriction.
  13. 13. α - aminoisobutyric acid (Aib).

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