PEPTIDOMIMETICS , BACKBONE MODIFICATION , LOCAL AND GLOBAL CONSTRAINTS OF PEPTIDES

1. jjj
Presented by: Souparnika 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

5. 4

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

8. 7

9.  Modifications at every part of single amino acid have been reported specifically:
1. The amino group can be replaced with isosteric atoms or groups, such as
oxygen, keto-methylene.
2. The alpha carbon with nitrogen atoms, C-alkyl to achieve quatenary amino
acids or boron atoms.
3. 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

12. 11

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

18. 17

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
1. 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
2. Ruzza P. Medicinal chemistry and drug design. P: 297 – 314.
3. 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
4. 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