Peptidomimetics Classification of Peptidomimetics Therapeutic values of Peptidomimetics Recent Advance in Peptidomimetics

1. PRESENTING TO
Mr. Purushotham K N
Assistant . Professor
Dept. of Pharmaceutical Chemistry
Sri Adichunchanagiri College of Pharmacy
PRESENTED BY
Mr. Darshan N U
M Pharmacy First Semester
Dept. Pharmaceutical Chemistry
Sri Adichunchanagiri College of Pharmacy
PEPTIDOMIMETICS
ADVANCE MEDICINAL CHEMISTRY

2. INTRODUCTION
• A peptidomimetics is a small protein-like chain designed to mimic a peptide.
✓ They are typically arise from modification of an exsisting peptide, or by designing
similar systems that mimic peptides, such as proteins and beta peptides.

3. • For e.g-anticancer peptidomimetics can bind to target proteins in order
to induced cancer celles into a form of programmed cell death called
apoptosis by mimcking key interactions that activate apoptotic
pathway in specified cells. This shows that peptidomimetics can play
vital role in treatment of various type of cancer.

4. ➢ TYPE –I PEPTIDOMIMETICS or PSEUDOMIMETICS-
▪ These are synthesized by structure based drug design.
▪ These peptidomimetics are closely similar to peptide backbone while retaining functional groups
that makes important contacts with binding sites of the receptors.
➢ Type-II peptidomimetics or functional mimetics:
▪ These peptidomimetics are synthesized by molecular modeling and high
throughput screening (HTS) etc.
▪ These are small non-peptide molecule that binds to a peptide receptor.
▪ Morphine was the first well-characterized example of this type of peptidomimetic.
CLASSIFICATION

5. Type-III peptidomimetics or topographical mimetics:
These are synthesized by structure based drug design which represents that they
possess novel templates, which appear unrelated to the original peptides but contain
the essential groups, positioned on a novel non-peptide scaffold to serve as
topographical mimetics.
Type-IV peptidomimetics or non-peptide mimetics:
These are synthesized by Group Replacement Assisted Binding (GRAB)
technique of drug design. These structures might share structural functional
features of type I peptidomimetics, but they bind to an enzyme form not
accessible with type I peptidomimetics for example piperidine inhibitors.

6. 1. Anti-microbial activity
Srinivas et al. developed some novel peptidomimetic antibiotics based on the antimicrobial peptide
protegrin I to combat the growing health threat posed by resistant pathogenic microorganisms. Several
rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative
Pseudomonas species.
2. Anti-malarial activity
Ettari et al. synthesized some novel peptidomimetics bearing a protected aspartyl aldehyde warhead leading
to the thioacylal and the acylal derivatives.Both Compounds proved to possess an increased antiplasmodial
activity with respect to the parent molecule.

7. 3. Anti-viral activity –
In the search for new and effective prodrugs against the herpes simplex virus, a series of acyclovir
analogues with a thiazole ring containing amino acids (glycine, alanine, valine, leucine) was
investigated by Georgi et al.

8. 4. Anti-cancer activity-
Yung-Feng et al. synthesized some novel unnatural amino acid-substituted
(Hydroxyethyl)urea peptidomimetics which inhibited secretase, the neuronal differentiation of
neuroblastoma cells and also interfered with tumorigenesis and the malignancy of
neuroblastomas. Which shows that these peptidomimetics can be used as lead compounds for
further development of novel anticancer drugs.

10. ➢ The physical and chemical properties of peptides and proteins and determined by the nature of the
constituents amino acids side chains and by the polyamide peptide backbone itself.
➢ The structure of the 20 primary amino acids are given in figure.Amino acid are divided into
hydrophobic and hydrophilic residues.
➢ Small peptides typically show high conformational flexibility due to the multiple conformations that are
energitically possible for each residues.
Fig.1-Backbone and side chain
torsional angles
Fig.2-Newman projection of three
staggered
rotamers in L-amino acids.

11. ❖ The backbone of isoelectric and isoelectronic substitution
❖ Various peptidomimetics or peptide bond surrogates, in which peptide bonds have been replaced
with other chemical groups,are designed and synthesized with the aim to obtain peptide analogs
with improved pharmacological properties.
❖ This is mainly because such approaches create an amide bond surrogate with defined 3
dimensional structures and with significant differences in polarity , hydrogen bonding
capability and acid-base character.
❖ Also important, the structural and stereochemical integrities of the adjacent pair of alpha carbon
atoms in these pseudopeptides are unchanged.
Modification Of Peptide Back Bone

12. LOCALLY RESTRICTIONS-
✓ The simplest constraints that can be placed on a given
residue involve the substitutuion of methyl group for an
hydrogen adjecent to a rotable bond.
✓ Example-
Replacing the alpha hydrogen on alanine with methyl group
gives alpha aminoisobutyric acid (aib).

13. GLOBAL RESTRICTIONS-
A) head-to-tail
B) Backbone-to-side chain
C) Side chain-to-side chain.

14. ❑This typically increases the in vivo stability of the cyclic peptides compared to their
linear analogs.
❑Cyclization can be obtained by connecting the N-with the C-terminus (head to tail)
portion of the peptide sequence ,or the couple of the 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. Recent Advance in Peptidomimetics
Peptides vaccines were developed for the prevention and treatment of pathogenicity
diseases, cancer and autoimmune disorders but because of low immunogenicity and
reduced bioavailability they have become unsuccessful peptidomimetics were
developed through chemical alteration of epitope structure to overcome this side
effects.
A new range of AMPs (antimicrobial peptides) termed “ peptidomimetics “ were
developed to mimic the bactericidal mechanism.

16. Conclusion
• In peptidomimetics, alterations to the side chain groups or the peptide backbone are used
to improve the peptide’s stability and/or biological activity. Since most linear peptides
can easily be degraded by enzymatic proteolysis, altering the peptide backbone can help
reduce their rate of degradation. The highly charged side chain groups on
peptidomimetics provide greater binding affinity and selectivity of the receptors towards
these peptidomimetics which will reduce unwanted side effects and improve the
therapeutic effects. As a result of their properties, peptidomimetics are of high interest as
bioactive agents and as drugs having pharmacological activities such as protease
inhibition, antimicrobial, anticancer, analgesics, antiviral and antimalarial activities etc.