Peptidomimetics by Yogesh.pptx

Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals
Shri Vile Parle Kelavani Mandal’s institute of Pharmacy, Dhule
Mr. Yogesh Kailas Chaudhari
(M-Pharmacy-Department Of Pharmaceutical Chemistry)
PRN-2254482823001
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Index
Sr.no. Particulars
1) Introduction
2) Definition
3) Classification
5) Therapeutics values of peptidomimetics
6) Strategic Approaches to Peptidomimetic Design
7) Examples of Peptidomimetic Drugs
8) References
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Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals 3
INTRODUCTION
A peptide is a short chain of amino acids, typically 2–50 amino acids. The amino acids
are linked together by chemical bonds called peptide bonds.
Peptides are different from proteins because they are shorter. Proteins are made from
one or more polypeptides, which are longer chains of amino acids (51 or more).
Peptides are naturally occurring and include many antibiotics, hormones, and other
substances that are involved in the biological functions of living beings.

• Peptides are a very important class of endogenous molecules that bind to a variety of
receptors in their action as neurotransmitters, hormones, and neuromodulators, and
there are numerous enzymes that are involved in the biosynthesis and catabolism of
these peptides.
• However, peptides generally do not make good drug candidates, especially as
orally administered drugs, because they are rapidly proteolyzed in the GI
tract and serum, and they are poorly bioavailable and rapidly excreted.
• In addition, many peptides can bind to multiple receptors, especially, to multiple
members of the same receptor family.
• What is needed is a compound that mimics or blocks the biological effect of a
peptide by interacting with its receptor or enzyme but does not have the
undesirable characteristics of peptides. This is a peptidomimetic.
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DEFINITION
• They are typically arise from modification of an existing peptide, or by designing similar
systems that mimic peptides, such as proteins and beta peptides.
• Peptidomimetics binds to enzymes or receptors with higher affinity than the starting
peptide. As an overall result, the native peptide effects are inhibited (antagonist or
inhibitor) or increased (agonist).
• 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.
“A peptidomimetics is a small protein-like chain designed to mimic a peptide.”
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• By tethering two amide nitrogen atoms with a linker (backbone to backbone)
• By introducing a chemical junction between a Cα and a nitrogen atom (backbone
to backbone)
• By linking an N-terminal amino group with an amide nitrogen atom with a spacer
(head to backbone)
• By cyclizing the two N- and C-terminal ends of a peptidomimetic structure with an
amide bond(head-to-tail)
Basic Approaches to modify peptides

CLASSIFICATION
TYPE-I PEPTIDOMIMETICS or PSEUDOMIMETICS:
• These are synthesized by structure based drug design.
• These peptidomimetics are closely similar to peptide backbone while rest 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.
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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 1
peptidomimetics for example piperidine inhibitors
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THERAPEUTIC VALUES OF PEPTIDOMIMETICS
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Therapeutic value (TV) is the difference in effectiveness between a new therapy
and the current treatment. It's also known as added therapeutic value (ATV). ATV
measures the therapeutic advantages of new medicines compared to existing ones
in terms of safety and comparative effectiveness.
1. Anti-microbial activity-
Srinivas et al. developed some novel peptidomimetic antibiotics based on the
antimicrobial peptide protegrin I in 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.
J. Chem. Pharm. Res., 2011, 3(6):173-186

Ettari et al. synthesized some novel peptidomimetics bearing a protected aspartyl
aldehyde warhead leading to the thioncylal and the acylal derivatives Both
Compounds proved to possess an increased antiplasmodial activity with respect to the
parent molecule.
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2. Anti-malarial activity-
J. Chem. Pharm. Res., 2011, 3(6):173-186

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.
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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.
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5. Selectivity for DNA receptors
A peptidomimetic template, consisting of a hydrophobic scaffold, a dansyl fluorophore, and an
Arg-His recognition strand, was tested by Jeffrey et al. as a simple mimic of zinc finger of the
protein. The DNA duplexes had weaker interactions with the free Arg-His recognition strand,
the dansyl functional group, and a scaffold that contained only glycines as the recognition
strand. The scaffold most likely provides for greater van der Waal's interactions, a larger
hydrophobic effect upon association, and reduces the freedom of motion of the side chains.
This last effect was confirmed by molecular mechanics calculations and by the fact that the
mimetic suffered a smaller loss of entropic energy upon association than the free recognition
strand. These studies show that the synthetic scaffold is a promising platform in which peptides
can be attached to increase their affinity and possibly selectivity for DNA targets

6. Aminopeptidase N inhibition activity:
The biological characterization for the piperidinedione peptidomimetic analogues was performed by
Qianbin et al. which revealed that most compounds displayed high inhibitory activity against
aminopeptidase N (APN). In addition, they also displayed good activity in HL-60 cell assay and in vivo
anti-metastasis assay. This interesting activity profile may also guide the design of new, specific inhibitors
of target mammalian aminopeptidases with ‘one-zinc’ active site.

Strategic Approaches to Peptidomimetic Design
A major effort in peptidomimetic chemistry is connected to 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. The overall result of this structural intervention is to stabilize the molecule with respect to metabolic
processes that occur in vivo, thus giving access to orally available drugs and compounds with improved
pharmacokinetics/pharmacodynamics (PK/PD) properties.
1. Modification of Amino Acids
2.Compounds with Global Restrictions
3.Molecular Scaffolds Mimicking the Peptidic Backbone
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1. Modification of Amino Acids
The structure of the 20 primary amino acids are given in figure. Amino acid are divided into hydrophobic and hydrophilic residues
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• Manipulation of the peptide structure with aim of reducing molecular recognition by proteases
and of introducing conformational restrictions is achieved locally by intervening on either
backbone or side-chains by introduction of modified aminoacids.
• 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.
Fig 1-Backbone and side chain torsional angles.
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Small peptides typically show high conformational flexibility due to the multiple conformations that are
energitically possible for each residues.
Fig. 2-Newman projection of three staggered rotamers in L-amino
acids.
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• B-Methylamino acids have been reported for restricting the conformations of a bioactive peptide through the
insertion of a stereocenter at the B-position.
• Indeed, four configurations are accessible by varying the two stereocenters; as an exemplificative entry to this
approach, the systematic incorporation of B-MePhe into somatostatin peptidomimetics has resulted in a
model for the ligand-receptor interaction, based on the changes in activity induced by different configurations
at the B centre.
• Substitutions of a-aminocycloalkane carboxylic acids varying in ring size (Figure-1.3) into various positions of
enkephalin (H -Tyr-Gly-Gly-Phe-Leu-OH) a peptide responsible for modulating pain response, resulted in a
peptidomimetic with greater in vivo activity.
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This has been approached 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 (Dtc) for Pro (Figure 1.4) in angiotensin II, a key peptide in
blood pressure regulation, resulted in a peptidomimetic with 39% greater agonist activity than
the natural peptide
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References
1. https://pubs.rsc.org/en/content/articlelanding/2021/QO/D1QO00892G
2. Peptidomimetics https://www.slideshare.net/AkshayYadav176/peptidomimetics-200
3. Peptidomimetics in Organic and Medicinal Chemistry by Wiley
4. J. Chem. Pharm. Res., 2011, 3(6):173-186
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