PEPTIDOMIMETICS.(MPHARM ,BPHARM,MSC,BSC

PEPTIDOMIMETICS , BACKBONE MODIFICATION , LOCAL AND GLOBAL CONSTRAINTS OF PEPTIDES

1. jjj Presented by: S ouparnika T Ist M.Pharm Pharmaceutical Chemistry PEPTIDOMIMETICS

2. CONTENTS Modification of the peptide backbone , Incorporating conformational constraints locally or globally. 1

3. INTRODUCTION A small protein -like chain designed to mimic a peptide. Arise either from - Modification of an existing peptide, By designing similar systems that mimics peptides, such as peptoids and β-peptides. 2

4. MODIFICATION OF PEPTIDE BACKBONE Backbone modification is done by introducing amide bond surogates with aim of improving the stability of peptide in –vivo. Several amide bond have been proposed that mimic the structural features of the peptide bond. In some circumstances modify the conformational profile and the hydrogen – bonding capacity too. 3

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6. The introduction of aliphatic moieties augments the conformational flexibility locally. Whereas, the application of olefin isosteres does not alter such topology. The hydrogen bonding capacities are modulated by applying diverse amide bond isosteres such as sulfonamide , phosphinic or peptoids , depending on the accessibility of donors or acceptors for such interactions. 5

7. Incorporating conformational constraints locally The most conservative approach to dealing with modifications of the peptide is the introduction of local structural changes. These modifications are restricted to single amino acids and thus are local alterations of the peptide structure . 6

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9. Modifications at every pa r t of single amino acid have been reported specifically: The amino group can be replaced with isosteric atoms or groups, such as oxygen, keto-methylene . The alpha carbon with nitrogen atoms, C-alkyl to achieve quatenary amino acids or boron atoms. The carbonyl group has been replaced with thiol , methylene , phosphinic and borinic groups. 8

10. 4. Retro- Inverso peptides have been also proposed, which consist of an amino acid moiety 9

11. Single amino acid Modification The approach of modifying a single amino acid unit within a peptide sequence is generally achieved by introducing constraining elements to reduce conformational flexibility. Backbone alkylation causes the angles ϕ, ψ, χ to be constrained, and N-alkylation facilitates cis/trans amide bond isomerism, whereas in the backbone Cα-alkylation ϕ, ψ are constrained to a helical or extended linear structure. 10

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13. Nα-Cα Cyclized Amino Acids The presence of a bond connecting Nα to Cα that forms a cycle responsible for the reduced conformational freedom around this amino acid. Rotation around the Cα –C=O bond is partially impaired for the non-bonded interaction between the carbonyl group and the ring. The steric hindrance between the proline mimetic and vicinal residues affects the overall conformation around this peptide sequence. 12

14. Some approaches Modulation of the ring size, ranging from aziridines to omoproline Inclusion of heteroatoms, such as azaproline or silaproline Introduction of substituents at positions 3, 4, 5 to improve the conformational restriction 13

15. α- Methylated Amino Acids • The α-hydrogen is replaced by a methyl group. Methylation severely restricts rotation around Nα -Cα (Φ) and Cα- C(O) (ψ) bonds of amino acid. • The AIB residue has been incorporated into numerous bioactive peptides. • Unlike AIB (a), all other α – methylated amino acids are chiral like isovaline (b) and α –methylphenylalanine (c). 14

16. α – α1 Dialkyl Glycine & Amino Cycloalkane Carboxylic Acids Replacement of 2 H atoms on the Cα atom of the glycine residue with identical alkyl or aryl groups results in α – α1 disubstituted glycine. 15

17. Dipeptide isosteres Scaffold approach in generating dipeptide isosteres resulted in a remarkable strategy to constrain the conformational freedom of a specific region of a peptide compound by blocking ϕ, ψ or ω rotations around backbone covalent bonds. From the Freidinger research, diverse molecules, such as lactams, piperazinones and imidazolinones, have been employed as molecular scaffolds capable of constraining the conformation around a dipeptide unit. 16

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19. Eg .Catalytic hydrogenolysis was employed to remove the side-chain Cbz protecting group, followed by the addition of glyoxylic acid to the reaction mixture to attain the newly formed amine moiety, in (2),This carboxy-methylated compound cyclized & warming in dimethylformamide (DMF), the δ-lactam dipeptide (3) in an overall yield. 18

20. . Retro-Inverso Peptides Retro-Inverso isomerization is a method for modifying the structure of the backbone to prevent the protease from recognizing the peptide-based inhibitor as a substrate. This can be achieved by replacing one or more L-amino acids with the parent enantiomer, and at the same time inverting the backbone direction from N → C to C → N. The Retro-Inverso modification does not lead to a more constrained polypeptide. Ex: Retro-Inverso peptidomimetic of the key tetrapeptide sequence found in gastrin. 19

21. Retro inverse peptides have the following feature: the reversal of amide bond direction minimizes degradation by enzyme peptidase thereby increasing mimetics in vivo half-life dramatically. 20

22. N- Methylation of Peptides The N- methylated amide bond often adopts cis, as well as trans geometry as with Nα-Cα , cyclized amino acid derivatives. Amino acid N- methylation also affects the rotation of Φ, ψ angles. In addition when the residue preceding the N-methyl amino acid, the torsion angle for the side-chain conformation is also severely restricted by N- methylated residue. The above conformational restrictions of N- methylated amino acids have been used to understand the molecular basis of the bioactivities of morphiceptin and demorphin . 21

23. Azapeptides Azapeptides are an interesting and synthetically easy approach to peptidomimetic design in which the Cα atom of the backbone is replaced isoelectrically by a nitrogen atom. 22

24. They can be synthesized very easily from substituted hydrazine or hydrazides , such as through the acylation of hydrazines and incorporation of aza -amino acid esters into a peptide chain. 23

25. Peptoids It can be described as mimetics of α-peptides in which the side chain is attached to the backbone amide nitrogen instead of the α-carbon. This modification results in the formal shift of the position of the side chain with respect to the parent peptide backbone. Peptoids were considered as an accessible class of molecules from which lead compounds could be identified for drug discovery. 24

26. Incorporating conformational constraints globally The macrocyclic peptide has several advantages in improving the quality of the bioactive compound in terms of bioavailability and potency, as the high proportion of cis amide bonds and the absence of free C- and N- terminal confer higher metabolic resistance. Cyclization between backbone elements is approached in several ways:- By tethering two amide nitrogen atoms with a linker (backbone to backbone) By introducing a chemical junction between Cα and a nitrogen atom (backbone to backbone) . 25

27. By linking an N-terminal amino group with amide nitrogen with a spacer (head to the backbone) By cyclizing the two N- and C- terminal ends of a peptidomimetic structure with an amide bond (head to tail). 26

28. References Peptidomimetics in organic and medicinal chemistry by Trabocchi A, Guarna A. The art of transforming peptides in drugs. 1st edition, Wiley publications. Pg. No: 3 - 35 Ruzza P. Medicinal chemistry and drug design. P: 297 – 314. Abdildinova A, Kurth MJ, Gong YD. Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications. Asian Journal of Organic Chemistry. 2021 Sep;10(9):2300-1 Avan I, Hall CD, Katritzky AR. Peptidomimetics via modifications of amino acids and peptide bonds. Chemical Society Reviews. 2014;43(10):3575-94. 27

29. 5. Ilker Avan, C. Dennis Hall, Alan R. Katritzky. Peptidomimetics via modifications of amino acids and peptide bonds. Journal is the royal society of chemistry 2014;43: 3575-3594. 6. Rajeev Kharb et al. Therapeutic importance of peptidomimetics in medicinal chemistry. 7. J. Chem. Pharm. Res., 2011, 3(6):173-186. 8. Lenci E, Trabocchi A. Peptidomimetic toolbox for drug discovery. Chemical Society Reviews. 2020;49(11):3262-77. 28