Peptidomimetics are small protein-like chains designed to mimic peptides but with greater stability and specificity. They are created either by modifying existing peptides or designing new structures that mimic peptides. Peptidomimetics incorporate conformational constraints locally or globally to restrict flexibility and exclude potential conformations, allowing for more targeted interaction with biological targets. Conformational constraints are needed to improve properties like stability, activity, and selectivity for applications like drug development and targeted cancer therapies. Common constraints include cyclization, disulfide bonds, and restricted amino acids.

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. 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.

6. • 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.

7. • 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.

8.  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

9.  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

11. 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

12. 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).

15. 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

16. • 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.

17. • 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.

18. • 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.

19. α - aminoisobutyric acid (Aib).