Peptidomimetics are compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space and which retain the ability to interact with the biological target and produce the same biological effect. Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide for example Stability against proteolysis (duration of activity) Poor bioavailability. Receptor selectivity or potency (often can be substantially improved).

1. ROHIT BHATIA
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
ISF COLLEGE OF PHARMACY
WEBSITE: - www.isfcp.org
EMAIL: bhatiarohit5678@gmail.com
ISF College of Pharmacy, Moga
Ghal Kalan,GT Road, Moga- 142001, Punjab, INDIA
Internal Quality Assurance Cell - (IQAC)
Peptidomimetics

2. Introduction
 Peptidomimetics are compounds whose essential elements
(pharmacophore) mimic a natural peptide or protein in 3D space
and which retain the ability to interact with the biological target
and produce the same biological effect.
 Peptidomimetics are designed to circumvent some of the
problems associated with a natural peptide for example
 Stability against proteolysis (duration of activity)
 Poor bioavailability.
 Receptor selectivity or potency (often can be substantially
improved).
2

3. Contd…
 The design process begins by developing structure–activity relationships (SAR) that
can define a minimal active sequence or major pharmacophore elements, and identify
the key residues that are responsible for the biological effect.
 Then structural constraints are applied to probe the 3D arrangement(s) of these
features. In this process, the peptide complexity is reduced and the basic
pharmacophore model is defined by its critical structural features in 3D space.
 This model then supports the re-assembly of the critical elements and non-peptide
variants on a modified scaffold that presents the optimized pharmacophore to the
receptor.
3

4. 4

5. 5Classification of Peptidomimetics

6. Type-I peptidomimetics or pseudopeptides
 These are synthesized by structure based drug design. These peptidomimetics
are closely similar to peptide backbone while retaining functional groups that
makes important contacts with binding sites of the receptors.
 Some units mimic shortportions of secondary structure of peptide for example
β-turns and have been used to generate lead compounds. Many early protease
inhibitors were designed from substrate/product mimeticsof the peptide bond
in a transition state or product state for the enzyme-catalyzed reaction.
 For example Pyrrolinones contains peptide-like side-chains that fit the active
sites of most peptidases and also these are resistant to normal proteolysis
because they replace amide bonds with metabolically stable units on amino
acid unit of parent peptides
6

7. Contd… 7

8. 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.
8

9. Contd…
 Initially, type I1 mimetics were considered to be direct structural analogs of the
natural peptide, b characterization of both the endogenous peptide and
antagonist's binding sites by site-directed mutagenesis indicate that antagonists
for a large number of receptors seem to bind to receptor subsites different than
those used by the parentpeptide.
 Consequently, functional mimetics may not mimic the structure of the parent
peptide. Despite this uncertainty, the approach has been quite successful and
produced a number of potential drug lead structures. For example G-protein
coupled receptor (GPCR) antagonists.
9

10. 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. Several type III peptidomimetic protease inhibitors have been characterized
where direct X-ray structural determination of both the peptide-derived inhibitor and the
heterocyclic non-peptide inhibitor complexes have been compared.
 These examples demonstrate that alternate scaffolds can display side-chains so that they
interact with proteins in fashion closely related to that of the parent peptide for example
non-peptide protease inhibitors.
10

11. Contd… 11
 It was shown to be essentially correct by applying the principle of conformational
restriction (Fig. 15.5). Deletion of the N-terminal dipeptide, followed by insertion of
the D-Trp at position-8, and replacement of the disulfide sulfurs with carbons
produced analog (9).
 NMR and other data suggested that the two Phe side-chains were clustered, thus they
were replaced by a transannular disulfide bond limiting the available conformation,
as in compound (10).
 After several iterations of this process, a biologically active cyclic hexapeptide (1 1)
was discovered that retained only 6 of the original 14 amino acids in somatostatin yet
produced a fully active derivative.

12. Type-IV Peptidomimetics or non-peptide
mimetics 12
 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 I peptidomimetics for example piperidine inhibitors

13. 13The Nonpeptide Renin Inhibitors

14.  Peptides tend to be quite comformationally flexible and conformations
are highly dependent on environment.
 The relationship or lack thereof of conformations in solution and the
receptor-bound conformation presents a major problem in this research.
 In most successful approaches to small molecule mimetics, the chemical
modifications involve the
Restriction of conformations
 Performed either by the cyclization of peptides
 The incorporation of conformationally restricted building blocks, mostly
unnatural amino acids and dipeptide surrogates
 The other tactic involves replacing a particular peptide bond with its
isoster.
14Contd….

15. Conformationally Restricted Peptides 15
 Replacement of L~Tryptophan in the position-8 of somatostatin by D-
tryptophan produced an analog that retained biological activity. This unusual
biological result is possible when a D,L-sequence (D-Trp-Lys) replaces an
L,L-sequence Trp-Lys) in a peptide at a type I1 p-turn, because the
topography of the amino acid side-chains at these positions is essentially
identical in these turns

16. 16

17. Contd…
 Introduction of a-methyl amino acid substituents into peptides
as a way to decrease the conformational space available to the
resulting peptide
 Replacement of the amino acids of the PI-P,‘ cleavage site by
D-amino acids or the employment of a-C or a-N alkylated
amino acids and cyclic or β-amino acids.
17

18. 18Representative amino acid mimetics

19. Contd…
 Mimicking the secondary structure of peptides has become one of the
most important tools for rational drug design.
 These methods induce the synthetic analog to adopt a set of target
conformations, which are designed to mimic the bioactive conformation
predicted in the native substrate from biophysicaltechniques.
 Molecular surrogates have been found that efficiently mimic turns, strands,
sheets, and helices. By far, the major efforts have focused on the design of
β-turn mimetic. Some of the templates used to constrainthe conformational
torsion angles of the peptide chain.
19

20. 20
Conformationally restricted ACE inhibitors

21. 21
Lactams as β-turn mimetics

22. 22
Other β-turn mimetic scaffolds

23. Contd… 23
γ-turn mimetic scaffolds.

24. Control of Absorbance 24
β-sheet mimetics

25. Contd…. 25
Newer templates found in helical or loop structures.

26. 26Peptide Bond Isosteres

27. 27Transition-state Analog Inhibitors

28. 28
TSA used to inhibit aspartic peptidases

29. 29
Peptide-derived TSA inhibitors used clinically in HW protease-based
AIDS therapies

30. 30
Cyclic urea as nonpeptide HIV protease inhibitors

31. Contd… 31
Angiotensin II inhibitors

32. 32
Unnatural amino acid substituted (Hydroxyethyl)urea peptidomimetics

33. 33

34. 34

35. 35
Inteleukin-1β converting enzyme inhibitors

36. 36