1Enhancing bioactive-peptide by
conformationally controlled mimetics
LITERATURE SEMINAR #3
Y.KAMIMURA

2020/8/5

2

1. Introduction
2. Major secondary structures and its mimetics
•••
•
•
•

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitorTurns
ǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
2020/8/5

3

1. Introduction
2. Major secondary structures and its mimetics
••
•
•
•
•

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitorTurns
ǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
2020/8/5

Introduction

4

Bioactive Peptides
ʘ-Conotoxin MVIIA:Neurotoxin

Enkephalin:Endogenous opioid peptide
Actinomycin D:Tumorsuppressants

NH2
H2NH
N

H2N

OO
HON
H
S O
O SH
N

H
N

O
N
H
O

N
H
O
HO HO

Somatostatin:Growth Hormone-Inhibiting Hormone

O
H
NO

O
N
H
O

H
N
O

N
H
HOH
NH
NNH
OO
HN
O

NH2

IPeptides show strong, wide spectrum of bioactivity.
2020/8/5

Ciclosporin:ImmunosuppressantsIntroduction

5Advantages of peptide as bioactive substance

9Limitless diversity
9The ease of synthesis and analysis
9Inherent biological relevance
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Zhou; P., Meng; Y., et al ., Mol. Omics, 2019, 15, 280

https://www.chem-station.com/odos/2013/11/-merrifield-solid-phase-peptid.html
Morimoto; J., Fukuda; Y., Sando; S., et al., J.A.C.S, 2019, 141, 14612

Introduction

6

Disadvantages of peptide as bioactive substance
H2N

LANA-FITC
O
H2N

N
H

H
N
O
HOFITC

NH

O

OH

ON
H
OH
O
N
H

MeNH

HN
H
NO
N
H

OO

H
NOSNHHNOO
H
NOH

HNO

HNNH2NH

HN
NH
H2N

X Low stability in cell/vivo

X Low bioavailability

X Immunogenicity

X Membrane permeability
2020/8/5

X High flexibility
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766
Fujiwara; Y, Kanai;M., et al, ChemRxiv, 2020

Zhou; P., Meng; Y., et al ., Mol. Omics, 2019, 15, 280
Sano; H, Imagawa; A., J. Diabetes Inv., 2019, 11, 281

Introduction

7

Pathway of the intestinal uptake of peptides

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Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766

Introduction

8

Peptidomimetics

2020/8/5

Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766
Verhoork; S.J.M, Coxon; C.R, et al., Chem. Euro. J., 2018, 25, 177

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
Chang; Y.S., Sawyer; T.K, et al., PNAS, 2013, 110, E3445

Introduction

9

Peptidomimetics

N-substituted alanine

2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

Introduction

10

Peptidomimetics

2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

Introduction

11

Mimicking Peptide-Protein Interactions

2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

12

1. Introduction
2. Major secondary structures and its mimetics
••
•
•
•
•

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor
TurnsǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
2020/8/5

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

13

ɲ-helix and its mimetics

2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

14

ɲ-helix in p53-MDM2 interaction

2020/8/5

Chène ; P., Nat. Rev. Cancer, 2003, 3, 102
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

15

Example: Sidechain Crosslinking

2020/8/5

Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

16

Example: Sidechain Crosslinking

Nutlin-3aI SAH-p53-8 can also bind to HDMX.
I HDM2 inhibition by Nutlin-3a can be compromised by overexpression of HDMX which do not bind to Nutlin-3a.
2020/8/5Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

17

Example: Sidechain Crosslinking
IMembrane permeable
IStabilized
ILow flexibility and highaffinity
WT

SAH-p53-5

SAH-p53-8

SAH-p53-5
2020/8/5

Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411
Bernal; F., Verdine; G.L., et al., JACS, 2007, 129, 2456

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

18

Sidechain crosslinking
Thiol based cross-links

Ring-closing metathesis based cross-link

Lactam cross-links

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Verhoork; S.J.M, Coxon; C.R, et al., Chem. Euro. J., 2018, 25, 177
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

19

ɲ-helix in Invasion of malaria parasite to host cell

Actin filament

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Angrisano; F., Baum; J., et al., PLOS ONE, 2012, 7, e32188
Boucher; L.E., Bosch; J., J. Str. Bio., 2015, 190, 93DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

20

N-terminal capping

IHydrogen-bond acceptor amino acids such asAsn, Asp are enriched at N-ƚĞƌŵŝŶĂůŽĨɲ-helix.
INucleation of helix by such interaction induceƚŚĞĨŽƌŵĂƚŝŽŶŽĨɲ-helix.
2020/8/5

Pham; T.K., Kim; Y., Bioorg. Chem., 2020, 101, 104024

Aurora; R., Rose; G.D., Protein Sci., 1998, 7, 21
Presta; L.G., Rose; G.D., Science, 1988, 140, 1632

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

21

Example: N-terminal capping

2020/8/5

Douse; C.H., Tate; E.W., et al., ACS Chem. Biol., 2014, 9, 2204

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

22&ŽůĚĂŵĞƌƐ;ɲͬɴ-peptides)

2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
Pu; J., Jiang; S., et al., viruses, 2019, 11, 705

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix23

ǆĂŵƉůĞ͗&ŽůĚĂŵĞƌƐ;ɲͬɴ-peptides)(Enfuvirtide, as control)

2020/8/5

Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

24

Foldamers (Peptoids)

2020/8/5

Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɲ-helix

25

Example: Foldamer (Peptoid)

2020/8/5

Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

26

1. Introduction2. Major secondary structures and its mimetics
•••
•
•
•

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitorTurns
ǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
2020/8/5

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-sheet27

ɴ-sheet2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-sheet

28

ɴ-sheet mimetics

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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-sheet

29

LANA peptide

ILANA peptide is nucleosome binding site of latency-associated nuclear antigen-1 (LANA-1)
ILANA-1 is a multifunctional protein involved in tumorgenesis by Kaposi's sarcoma-associatedherpesvirus(KSHV).
2020/8/5

PDB: 1ZLA X-ray Structure of a Kaposi's sarcoma herpesvirus LANA peptide bound to the nucleosomal core
White; M.K., Khalili; K., Clin. Microbiol. Rev., 2014, 27, 463

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-sheet

30

Example: Macrocyclization

Competition to LANA(1-23)-FITC, Kd=2.5uM
H2N

H2N

NH

HNOHONHHOOHOO

H
NN
HOS

92020/8/5ONHOMeOHNOH
N

H2N

Kd,(LANA(1-23)-FITC)=200nM

NH

HN

H
NO
HN
H2NN
H

OH

O
HN

HN

OO
NH
HNNH

N
H

NH2O
N
H

OHOO
N
H

HO
H
N

N
H

O
S

12OO

H
N

MeO

H
N

H
N
O
HN
H2N

N
H

IC50,(9)=614nM

OH

IC50,(12)=204nM

HN

O

O
N
H

NH
HN

NH

NH2ISimple macrocyclization
increased the affinity 3-fold.

Yakushiji; F., Ichikawa; S., et al., Bioorg. Med. Chem., 2020, 30, 126839

31

1. Introduction
2. Major secondary structures and its mimetics••••••

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor
TurnsǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
2020/8/5

Mimetics of secondary structure: Turn32

Turn and its mimeticsIdƵƌŶƐĂƌĞŽĨƚĞŶĨŽƵŶĚĂƐƐƵďƐƚƌƵĐƚƵƌĞƐŽĨɴ-sheets.
ITurns often play crucial role in presenting hotspot residues.
2020/8/5

Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn33

ůĂƐƐŝĨŝĐĂƚŝŽŶŽĨɴ-turns by Venkatachalam
III’II

VIa1

VIII

VIa2

I’

VIb

2020/8/5

Bravern; A.G., Sci. Rep., 2016, 6, 33191

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn34

Somatostatin

Acromegaly

Pituitary gigantism
2020/8/5

Schonbrunn; A., Enc. Bio. Chem., 2013, pp.262
Kumar; U., Singh; S., Int. J. Mol. Sci., 2020, 21, 2568
Weckbecker; G, Bruns; C., et al., Nat. Rev. Drug Discov., 2003, 2, 999 Chanson; P., Salenave; S., Orphanet J. Rare Dis., 2008, 3:17

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn35

Intrinsic macrocyclization
NH2
H2N
H
N

H2NO

O

H
NO

NNH
H
Me S OMeO SO
HNHONHOHO HOO
HNO
NHOO

HNON
HHOOHNO

H
NOO
H
NNH

HN
NH2O

NH2H2N
H
N

H2N

O
NH

OO
HO2020/8/5HN
O
HNO
N
H
ON
H
OHO HOO

NHO

HN
O

N
H
HOH
NOO
H
N

NH

HN
O

NH2Rivier; J., Guillemin; R., et al., J. Med. Chem., 1975, 18, 123DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn36

Stabilization of macrocycle
NH2
H2N

R
X
R12020/8/5

H
NO
Y
H
NO
34N 5H
O

13N
H
O
HO HO

O
H
N

O
6O

N 7H
O

H
12 N

11O

NHHOH
N 8NH
OO

H
10 N

HN
9ONH2Veber; D.F, Hirschmann; R., et al., JACS, 1976, 98, 2367

37DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turnD-Trp at i+1 position improved the activity
NH2H2NOHN

H2N 1O2HO3NHS OO SHN
14OHN
413N 5HONHO
HO HOO
HNO
6OH

1112 NO

N 7HO
NH
HOH
N 8NHOO
H

HN

10 N

9O

NH2lD-ĂŵŝŶŽĂĐŝĚĂƚŝнϭƉŽƐŝƚŝŽŶŝƐŬŶŽǁŶƚŽďĞƐƚƌŽŶŐŝŶĚƵĐĞƌŽĨɴ-turn structure.
lIntroduction of D-Trp at position 8 improved the activity by 8-fold.
2020/8/5Rivier; J., Vale; W., et al., Biochem. Biophys. Res. Commun., 1975, 65, 746

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn38

Search for active conformation
NH2NH2NH2H2N

O

HNO
H
N13OHOH
N5NH
S
O4NH

OO
SH
N
12N 7H

6O

11NH
HOO

H
N 8H
NNH
OO

O

HN
H
9N10O

NH2O

H
N

413NH
O

NH
O
HO HOO
O
H
5N 6O
H
N
12S
S

N 7H
O

11 N
H
O
HOH
N 8O
HN
H
9N
10O

VI, V (Cys=Cys(Acm))

III, IIa (CysїCys(Acm))OH
NNHONH2NH5OHNH
N 8N 7HOOOO
SSOO
HNH
HH
11139NNNN
N12HH 10OOOHO HO46NH

NH2IV, IIb (Cys=Cys(Acm))

NH2H2NO

HNOH
N413NHONHOHO HOO
H
5 N
6O
H
N12O11O

N 7HONH
HOH
N 8OHN
H
9N10O

NH
O
NH2Cyclic analog

2020/8/5

Veber; D.F, Hirschmann; R., et al., PNAS, 1978, 75, 2636

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn39

Extraction of the essential structurelShorter bi-cyclic peptide resulted in ca. 2.5fold increase in the activity.

NH2O

H
NO
H
N413O
HO5NHSONH

6OS
HN12OH
N11ON 7HONHHOOO

H
10 N

HN
9NH2OI

2020/8/5NH

12OH
N5H
N 8O6H
N11O

N 7HO
NH
HOH
N 8NH
OO

H
10 N

O S

HN
9OIIa

H
N 65H
N

NH212O
N 7H
S O

11 NOHHOH
N8NHOO

H
10 N

HN
9O

NH2III

Veber; D.F, Hirschmann; R., et al., Nature, 1979, 280, 512

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn40DĂĐƌŽĐǇĐůŝǌĂƚŝŽŶďǇɴ-turn inducing amino acids
OH
NN
HNNH
O

OOO

HNNH
HOHN
NH2O

8H2NONH

ON

N
HOO
N
H

Pasireotide

2020/8/5

HN

H
NNH
OO

lIncorporation of turn inducing sequence
resulted in improved effect p.o.

HNO

NH2O

Veber; D.F, Hirschmann; R., et al., Nature, 1981, 292, 55
Lewis; I., Bruns; C., et al., J. Med. Chem., 2003, 46, 2334

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn41

Further improvement by N-Methylation
ONN
HOO
N
HO8NHOO
NH
N112020/8/5

N769NH210O8Biron; E., Kessler; H. et al., ACIE, 2008, 47, 2595

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn42

Relation between secondary structure and bioavailability
type II’ɴ-turnO
6Phe11їD-PheN

7

NHOO

11

N 10MeHOMeN 8NHOO
Me NH9NONH2

Loss of binding affinity
Loss of bioavailability

lThe conformation shown above seems to have effect on bioavailability.
lThe turn structure is the same as orally available peptide cyclosporin A.
lAlteration of turn type resulted not only in the loss of binding affinity but also inthe loss of bioavailability.
2020/8/5

Biron; E., Kessler; H. et al., ACIE, 2008, 47, 2595
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn43

Relation between secondary structure and bioavailability

lNone of the parameters could not solely explain the tendency.
lMethylation of N atom adjacent to D-Ala was common among the permeable peptides.
2020/8/5

Beck; J.G, Kessler; H., et al., JACS, 2012, 134, 12125
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn44

Relation between secondary structure and bioavailabilitylϮŽĨϯďŝŽĂǀĂŝůĂďůĞĂŶĚĐŽŶĨŽƌŵĂƚŝŽŶĂůůǇƵŶŝĨŽƌŵƉĞƉƚŝĚĞƐŚŽǁĞĚɴ//͛-ɴs/
turn structure.
lThe structure is the same as cyclosporin A and the somatostatin analog.
2020/8/5

Beck; J.G, Kessler; H., et al., JACS, 2012, 134, 12125
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn45

Shielding of solvateable NH of lipophilic peptide improve permeability

lBlocking of NH does not generally improve bioavailability.
2020/8/5

Rezail; T., Lokey; R.S., et al., JACS, 2006, 128, 2510
Marelli; U.K., Kessler; H., et al., Chem. Euro. J., 2015, 21, 8023

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn46Turn inducing amino acids
NH2R1R1O
NH
O

Ni

N
Hi+1O

O
Hi+3 N

i+2R4O

NH

O

R
R1N
H
Oi

H
i+3 N

i+2R4OOO
i+2R4OO

O

R2i+1H
i+3 N

NO

N

N
Hii+1R2O

O
HN

H
i+3 N

i+2R4OR3Nii+1O

O

Hi+3 N

R4Proteinogenic

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N
Hi+1H
N

R1H
NiNi+2OO
NH
R3Non-Proteinogenic
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn47

Tendency of turn induced by Pro-Xaa sequencelInduction of turn can be controlled, and indeed there are some major and strong turninducer, the structure of turn induced will usually be highly dependent on the context.
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Metrano; A.J., Miller; S.J., et al., JACS, 2017, 139, 492

DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞ͗ɴ-turn48

N-Methylation
R1N
H
Oi

O

R2i+1Hi+3 Ni+2R4ONO

R1H
Ni

NHOO

R1NH

R1HN

R2i+1OO
Hi+3 N

i+2R4ONR

NHOi+1OO
Hi+3 Ni+2R4O

NR1R1Nii+1R2OO
N

Hi+3 Ni+2R4O

lN-Methylation can be seen as a surrogate of proline.
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NiNH
O

Nii+1R2OO

O

N

Hi+3 Ni+2R4O

NH

R3Nii+1R2O

O
HN

Hi+3 Ni+2R4OR3

52

1. Introduction
2. Major secondary structures and its mimetics••••••ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor
TurnsǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
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SummarylStereopopulation controlled mimetics of peptide by the various artificial
motifs improve the properties of peptides.
l Affinity, Bioavailability and membrane permeability, Metabolic stability, Immunogenicity

lFor biological activity, rigidifying the structure at its active form is crucial.
lFor bioavailability and membrane permeability,
l Conformational rigidity and scarcity of solvateable NH (N-methylation, intramolecular hydrogenbonding, steric shielding)l Lipophilicity (lipophilic sidechains)l ^ƉĞĐŝĨŝĐĐŽŶĨŽƌŵĂƚŝŽŶ;Ğ͘Ő͘ɴ//͛-ɴs/ turn structure with cis peptide bond)have a positive effect in general.
lThe effect of each factor depends on the dominant transport pathway.
lFor metabolic stability, unnatural structure is effective on the whole.
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53

54

1. Introduction
2. Major secondary structures and its mimetics
•
••
•
•
•

ɲ-helixǆĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor
ɴ-sheetǆĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor
TurnsǆĂŵƉůĞŽĨɴ-turn mimetics

3. Summary
4. Appendix
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Appendix55

Synthesis of SAH-p53-x

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Appendix

56

Structure of Enfuvirtide

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Appendix

57

Synthesis Oligo N-substituted Glycine

PyBOP or PyBropSPPS

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Simon; R.J., Bartlett; P.A., et al., P.N.A.S, 1992, 89, 9367

Appendix

58

Only example of highly potent inhibitor made of oligo-NSG

ɲ1-adrenergic receptor

ʅ-opiate receptor
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Zuckermann; R.N., et al., J. Med. Chem., 1994, 37, 2678

Appendix

59

Synthesis of Oligo N-substituted Alanine

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Morimoto; J., Fukuda; Y., Sando; S., et al., J. A. C. S, 2019, 141, 14612

Appendix

60

Other foldamers

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Gangloff; N, Luxenhofer; R., et al., Chem. Rev., 2016, 116, 1753

Appendix

61

C,D-ƚǇƉĞŵŝŵĞƚŝĐƐŽĨɲ-helix

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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896

Appendix

62

C,D-ƚǇƉĞŵŝŵĞƚŝĐƐŽĨɲ-helix

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Appendix63ƉƉĞŶĚŝǆ͗WŽƉƵůĂƚŝŽŶŽĨɴ-turns

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Bravern; A.G., Sci. Rep., 2016, 6, 33191