This document discusses peptidomimetics, which are compounds that mimic peptides and proteins while overcoming issues like stability and bioavailability. It defines peptidomimetics and explains their therapeutic values, including antimicrobial, anticancer, antiviral, and analgesic activities. The document also describes two main approaches to designing peptidomimetics: manipulating amino acids, such as substituting them or modifying side chains, and mimicking the peptide backbone through replacements like esters or heterocycles. Specific examples of amino acid and backbone modifications that produce bioactive peptidomimetics are provided.

1. KLE COLLEGE OF PHARMACY, BELAGAVI
(Constituent unit of KLE Academy of Higher Education and Research,
Belagavi. Deemed-to-be University)
PEPTIDOMIMETIC’S
ADVANCED MEDICINAL CHEMISTRY
SEMINAR-IV
Presenter:
Aparna A Inamdar
ND0121002
M-Pharm(I-Semester)
(Department Of Pharmaceutical Chemistry)

2. CONTENTS:
Introduction to
Peptidomimetics
Therapeutic
values of
Peptidomimetics
Design of
Peptidomimetics
by manipulation
of amino acids
Modification of
peptide
backbone

3. DEFINITION
• Peptidomimetics are compounds whose essential elements (pharmacophore) mimic
natural peptide or protein in a 3D space and which upon modification, retain the
ability to interact with the biological target and produce the same biological effect as
that of the natural protein or peptide.1
• And these peptidomimetics binds to enzymes/ receptors with the higher affinity than
the previous peptide. And overall it leads either increase(agonist) or
decrease(inhibition) in the activity.

4. • Apart from being much more selective, efficient and lowered enzymatic
degradation than native peptides, they also results in fewer side effects.
• Peptidomimetics are mainly designed to overcome some of the problems associated
with natural peptides and proteins such as stability problems and poor oral
bioavailability, receptor selectivity and potency issue Etc.2

5. THERAPEUTIC VALUES OF PEPTIDOMIMETICS.3
 The various types of pharmacological activities displayed by peptidomimetics have
been discussed as below:
1. anti-microbial activity: Srinivas et al, developed some novel peptidomimetic
antibiotics based on the anti-microbial activity of the peptide called as
PROTEGRIN-I to combat against the drug resistant pathogenic gram-negative
pseudomonas species.

6. 2. Anti-cancer activity:
• Yung-fung et al, synthesized some novel unnatural amino acid substituted with
(hydroxyethyl) urea peptidomimetics which inhibits the secretase enzyme,
responsible for neuronal differentiation(division) of neuroblastoma cells. and also
interferes with the tumorigenesis process and malignancy of neuroblastomas. Hence
these peptidomimetics are used as lead compounds for further development of anti-
cancer drugs. P1 = Phenyl

7. 3. Anti-viral activity:
• Georgi et al, while in search of newer and effective prodrugs against the herpes
simplex virus synthesized a series of acyclovir analogues with a thiazole ring
containing amino acids (glycine, alanine, valine, leucine) peptidomimetics which
were tested for its anti-viral activity at the pH range from 1-7.4 pH and temp. of 370
c which were unstable under acidic conditions, and underwent hydrolysis from Gly-
thiazole-acyclovir, Ala-thiazole-acyclovir, Leu-thiazole-acyclovir to acyclovir. But
only Val-thiazole-acyclovir was stable at pH 7.4 and highly stable than the
valacyclovir (prodrug of acyclovir).

8. Gly-thiazole-acyclovir Ala-thiazole-acyclovir
Val-thiazole-acyclovir Leu-thiazole-acyclovir
Structures:

9. 4. Immuno detection activity:
• Murali et al, found out that antibody like binding peptidomimetics(ABiPs) such as
Anti-Her2/neu peptidomimetic(AHNP) which is a mimic of Herceptin, mAb used
for the advanced breast cancer therapy. And these Herceptin’s are also used to
detect the Her2/neu antigen using immuno detection amplification technique.
• hence, these ABiPs mimics the Herceptin’s so they are used as alternatives for
these monoclonal antibodies as a therapeutics, antigen-detection, target validation
and drug development.

10. 5. Analgesic activity:
• Duggan et al, reported the synthesis and biological activity of a low molecular weight
non-peptidic drug but it mimics the analgesic peptide ω-conotoxin GVIA. The
molecular weight of this compound is reduced to 5.3 μg/mol from 193 μg/mol and this
non-peptidic molecule produces EC50 value at the molecular weight of 5.3 μg/mol.
Also, its synthesized by only 6 step reaction but the peptidic ω-conotoxin GVIA is
synthesized by 13 step reactions which too time consuming process.

11. Structures:
13 step synthesis
6 step synthesis

12. DESIGN OF PEPTIDOMIMETICS.3
• A major effort in peptidomimetic chemistry is the development of compounds capable of
replacing one or more amino acids in a peptide sequence without altering the biological
activity of the native peptide. These all structural changes leads to stabilize the molecule
with respect to metabolic processes that occur in vivo, thus increases orally availability
of drugs along with improved pharmacokinetics/pharmacodynamics (PK/PD) properties.
• Peptidomimetics are designed mainly by two ways
a. Manipulation of amino acid
b. Manipulation of peptide backbone

13. 1. BY MANIPULATION OF AMINO ACIDS.4
• Manipulation of the peptide structure with aim of reducing its metabolism by
protease and other enzymes and of introducing conformational restrictions is
achieved locally by changing on either backbone or side-chains by introduction of
modified amino acids.
• Here, Cα-alkylated, Cβ-alkylated, Nα-alkylated amino acids are introduced.

14. By manipulation of amino acids continued..
• Ex: substitution of α-amino cycloalkane carboxylic acids varying in ring size into
various positions of ENKEPHALIN (H-Tyr-Gly-Gly-Phe-Leu-OH), results into
formation of a peptide responsible for modulating pain response, and
peptidomimetic with greater in vivo activity.

15. Structures of Amino acid mimetics:
N-methyl amino acid D-methyl amino acid α-alkyl amino acid α- amino acid
Cyclic amino acids
α-alkyl amino acid

16. By manipulation of amino acids continued..
• β-methyl amino acids have been used for restricting the conformations of a
bioactive peptide through the insertion of stereocenter at the β-position. and here we
get four configurations by varying the two stereo centers;
• an example to this approach, the incorporation of β-Me-Phe into somatostatin
peptidomimetics leads to the changes in one of the stereo-center and forms a model
for the ligand-receptor interaction.
• And changes in other stereo-center leads to the changing of the activity of the
peptide by formation of different configurations due at β-center.

17. By manipulation of amino acids continued..
• Proline analogues have been proposed with the aim of orienting the equilibrium
towards preferred geometry, generally the cis form has more importance in peptide
folding. Cis form can be achieved by varying the ring size, the substitution pattern
around the cyclic backbone and introducing heteroatoms.
• For example, the substitution of 5,5-dimethylthiazolidine-4-carboxylic acid in
angiotensin II resulted in a peptidomimetic with 39% greater agonist activity than the
natural peptide.
Proline 5,5-dimethylthiazolidine-4-carboxylic acid

18. 2. BY MIMICKING THE PEPTIDE BACKBONE.5
• Mimicking the peptide backbone: is mainly done by just changing in the side chain by
amide bond replacements and keeping the backbone constant.
• although, there are quite a number of amide bond replacements are reported, the most
widely used surrogates, namely aminomethylene, oxomethylene, thiomethylene, keto
methylene, ester, sulfoxide, sulfonamide, thioamide, tetrazole, other heterocycles, beta-
amino acids, α-aminophosphinic acids, and phosphonamidates.
• These surrogates has its own unique physicochemical properties that need to be considered
before incorporation into a peptide chain.

19. The backbone of the peptide can be modified in various ways by isosteric or isoelectronic
substitution
Cyclization
N-allylation
Backbone extension Carbonyl replacement

20. By mimicking the peptide backbone continued..
Heterocyclic generation
N-methyl
Cα-replacement
Cα-substitution

21. REFERENCES
1. Peptidomimetics-
http://www.slideshare.net/ISFCPISFCollegeofPha/peptidomimetics?from_m_app=android
- accessed on-24/01/2022
2. Guarna A, Trabocchi A. Peptidomimetics in Organic and Medicinal Chemistry: the art of
transforming peptides in drugs. John Wiley & Sons; 2014 Mar 14.
3. Kharb R, Rana M, Sharma PC, Yar MS. Therapeutic importance of peptidomimetics in
medicinal chemistry. J. Chem. Pharm. Res. 2011;3(6):173-86.
4. http://www.slideshare.net/MahendraMahi28/peptidomimitics?from_m_app=android
5. Avan I, Hall CD, Katritzky AR. Peptidomimetics via modifications of amino acids and
peptide bonds. Chemical Society Reviews. 2014;43(10):3575-94.

22. THANK YOU