Peptidomimetics by Yogesh.pptx

Design Of Peptidomimetics

1. Shri Vile Parle Kelavani Mandal’s institute of Pharmacy, Dhule Shri Vile Parle Kelavani Mandal’s institute Of Pharmacy, Dhule Approved by PCI,AICTE,DTE Affiliated to Dr. Babasaheb Ambedkar Technological University, Lonere PRESENTED BY M r . Yogesh Kailas Chaudhari (M- P harmacy-Department O f Pharmaceutical Chemistry) PRN -225448282 30 1 Peptidomimetics 1

2. Index Sr.no. Particulars 1) Introduction 2) Definition 3) Classification 5) The rapeutics values of peptidomimetics 6) Strategic Approaches to Peptidomimetic Design 7) Examples of Peptidomimetic Drugs 8) References 2

3. 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.

4. 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 . 4

5. 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. ” 5

6. 6 B y tethering two amide nitrogen atoms with a linker (backbone to backbone) B y introducing a chemical junction between a Cα and a nitrogen atom (backbone to backbone) B y linking an N-terminal amino group with an amide nitrogen atom with a spacer (head to backbone) B y cyclizing the two N- and C-terminal ends of a peptidomimetic structure with an amide  bond(head-to-tail) Basic Approaches to modify peptides

7. CLASSIFICATION TYPE-I PEPTIDOMIMETICS or PSEUDOMIMETICS : These are synthesized by structure based drug de sign. These peptidomimetics are closely similar to peptide backbone while re s t 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 . 7

8. 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 A ssisted 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 8

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10. THERAPEUTIC VALUES OF PEPTIDOMIMETICS 10 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

11. 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 antipla s modial activity with respect to the parent molecule. 11 2. Anti-malarial activity - J. Chem. Pharm. Res., 2011, 3(6):173-186

12. 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 . 12

13. 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. 13

14. 14 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

15. 15 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.

16. 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 16

17. 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. 17

18. 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-Back b one and side chain tor sional angles . 18

19. 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 rota mers in L-amino acids . 19

20. 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 . S ubstitutions of a- aminocycloalkane carboxylic acids varying in ring size ( Figur e- 1.3) into various positions of enkephalin (H -Tyr- Gly -G ly - Phe - Leu -OH) a peptide responsible for modulating pain response, resulted in a peptidomimetic with greater in vivo activity . 20

21. 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 21

22. References https://pubs.rsc.org/en/content/articlelanding/2021/QO/D1QO00892G Peptidomimetics https://www.slideshare.net/AkshayYadav176/peptidomimetics-200 Peptidomimetics in Organic and Medicinal Chemistry by Wiley J. Chem. Pharm. Res., 2011, 3(6):173-186 22

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