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Enhancing bioactive-peptide by conformationally controlled mimeticsLITERATURE SEMINAR #3
Y.KAMIMURA
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
Bioactive PeptidesIntroduction
Enkephalin:Endogenous opioid peptide
Ciclosporin:Immunosuppressants
Actinomycin D:Tumorsuppressants
ʘ-Conotoxin MVIIA:Neurotoxin
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HN
NH
HN
NH
HN
NH
HN
H2NO
O
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
OHO
OSS
NH2H2N
O
NH
NH2
HOHOHOSomatostatin:Growth Hormone-Inhibiting Hormone
IPeptides show strong, wide spectrum of bioactivity.
Advantages of peptide as bioactive substance
9Limitless diversity9The ease of synthesis and analysis9Inherent biological relevance
Introduction
https://www.chem-station.com/odos/2013/11/-merrifield-solid-phase-peptid.htmlMorimoto; J., Fukuda; Y., Sando; S., et al., J.A.C.S, 2019, 141, 146122020/8/5
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Zhou; P., Meng; Y., et al ., Mol. Omics, 2019, 15, 280
Disadvantages of peptide as bioactive substance Introduction
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766Fujiwara; Y, Kanai;M., et al, ChemRxiv, 2020
Zhou; P., Meng; Y., et al ., Mol. Omics, 2019, 15, 280Sano; H, Imagawa; A., J. Diabetes Inv., 2019, 11, 2812020/8/5
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X Low bioavailability
X Membrane permeability
X Low stability in cell/vivo
X High flexibility
NH
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHO
O
OH
OH
HN NH2
NH
HN
H2NNH
SMe
HN
H2N
NH
OH
OH2N
NHFITC
X Immunogenicity
LANA-FITC
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
PeptidomimeticsIntroduction
Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766Verhoork; S.J.M, Coxon; C.R, et al., Chem. Euro. J., 2018, 25, 177
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896Chang; Y.S., Sawyer; T.K, et al., PNAS, 2013, 110, E34452020/8/5
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PeptidomimeticsIntroduction
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 88962020/8/5
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N-substituted alanine
PeptidomimeticsIntroduction
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 88962020/8/5
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Mimicking Peptide-Protein InteractionsIntroduction
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 88962020/8/5
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
ɲ-helix and its mimeticsDŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 88962020/8/5
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ɲ-helix in p53-MDM2 interaction
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Chène ; P., Nat. Rev. Cancer, 2003, 3, 102Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Example: Sidechain Crosslinking
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Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Example: Sidechain Crosslinking
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Nutlin-3a
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
ISAH-p53-8 can also bind to HDMX.IHDM2 inhibition by Nutlin-3a can be compromised by overexpression of HDMX which do not bind to Nutlin-3a.
Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
Example: Sidechain Crosslinking
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Bernal; F., Walensky; L.D., et al., Cancer Cell, 2010, 18, 411Bernal; F., Verdine; G.L., et al., JACS, 2007, 129, 2456
WT SAH-p53-8SAH-p53-5
IMembrane permeableIStabilizedILow flexibility and high affinity
SAH-p53-5
Sidechain crosslinking
Verhoork; S.J.M, Coxon; C.R, et al., Chem. Euro. J., 2018, 25, 177Pelay-Gimeno; M, et al., ACIE, 2015, 54, 88962020/8/5
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Thiol based cross-links Ring-closing metathesis based cross-link
Lactam cross-links
ɲ-helix in Invasion of malaria parasite to host cell
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Angrisano; F., Baum; J., et al., PLOS ONE, 2012, 7, e32188Boucher; L.E., Bosch; J., J. Str. Bio., 2015, 190, 93
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Actin filament
N-terminal capping
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Aurora; R., Rose; G.D., Protein Sci., 1998, 7, 21 Presta; L.G., Rose; G.D., Science, 1988, 140, 1632
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Pham; T.K., Kim; Y., Bioorg. Chem., 2020, 101, 104024
IHydrogen-bond acceptor amino acids such as Asn, Asp are enriched at N-ƚĞƌŵŝŶĂůŽĨɲ-helix.
INucleation of helix by such interaction induce ƚŚĞĨŽƌŵĂƚŝŽŶŽĨɲ-helix.
Example: N-terminal capping
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Douse; C.H., Tate; E.W., et al., ACS Chem. Biol., 2014, 9, 2204
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
&ŽůĚĂŵĞƌƐ;ɲɴ-peptides)
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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896Pu; J., Jiang; S., et al., viruses, 2019, 11, 705
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
džĂŵƉůĞ&ŽůĚĂŵĞƌƐ;ɲɴ-peptides)
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Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
(Enfuvirtide, as control)
Foldamers (Peptoids)
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Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɲ-helix
Example: Foldamer (Peptoid)
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Morimoto; J., Fukuda; Y., Sando; S., et al., JACS, 2019, 141, 14612Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
ɴ-sheet
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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
ɴ-sheet mimetics
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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
LANA peptide
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PDB: 1ZLA X-ray Structure of a Kaposi's sarcoma herpesvirus LANA peptide bound to the nucleosomal coreWhite; M.K., Khalili; K., Clin. Microbiol. Rev., 2014, 27, 463
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-sheet
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-associated herpesvirus(KSHV).
H2NHN
NH
HN
NHO
O
O
O OHN
O
NH
HN
ONH
OHN
ONH
O
HN
H2NNH
HOOH
SMe
NHNH2
HN
HO
HO
O
HN
H2N
NH
NH
HN
NH
HN
NHO
O
O
O OHN
O
NH
HN
ONH
OHN
OHN
O
HN
H2NNH
HOOH
SMe
NHNH2
HN
HO
HN
H2N
NH
O
Example: Macrocyclization
Yakushiji; F., Ichikawa; S., et al., Bioorg. Med. Chem., 2020, 30, 1268392020/8/5
30 DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-sheet
9
Competition to LANA(1-23)-FITC, Kd=2.5uM
Kd,(LANA(1-23)-FITC)=200nM
IC50,(9)=614nM
IC50,(12)=204nM
ISimple macrocyclization increased the affinity 3-fold.12
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
Turn and its mimetics
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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
Mimetics of secondary structure: Turn
IdƵƌŶƐĂƌĞŽĨƚĞŶĨŽƵŶĚĂƐƐƵďƐƚƌƵĐƚƵƌĞƐŽĨɴ-sheets.ITurns often play crucial role in presenting hotspot residues.
ůĂƐƐŝĨŝĐĂƚŝŽŶŽĨɴ-turns by Venkatachalam
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I
II
VIII
I’
II’
VIa1
VIa2
VIb
Bravern; A.G., Sci. Rep., 2016, 6, 33191
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
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Schonbrunn; A., Enc. Bio. Chem., 2013, pp.262Weckbecker; G, Bruns; C., et al., Nat. Rev. Drug Discov., 2003, 2, 999
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Kumar; U., Singh; S., Int. J. Mol. Sci., 2020, 21, 2568Chanson; P., Salenave; S., Orphanet J. Rare Dis., 2008, 3:17
Somatostatin
Pituitary gigantism
Acromegaly
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Rivier; J., Guillemin; R., et al., J. Med. Chem., 1975, 18, 123
HN
NH
HN
NH
HN
NH
HN
H2NO
O
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
OHO
OSS
NH2H2N
O
NH
NH2
HOHOHO
Me Me
HN
NH
HN
NH
HN
NH
HN
H2NO
O
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
OHO
O
NH2H2N
O
NH
NH2
HOHOHO
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Intrinsic macrocyclization
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Veber; D.F, Hirschmann; R., et al., JACS, 1976, 98, 2367
RHN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
R1
XY
NH2H2N
O
NH
NH2
HOHOHO
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Stabilization of macrocycle
8
91011
1213
76
543
lD-ĂŵŝŶŽĂĐŝĚĂƚŝнϭƉŽƐŝƚŝŽŶŝƐŬŶŽǁŶƚŽďĞƐƚƌŽŶŐŝŶĚƵĐĞƌŽĨɴ-turn structure.
lIntroduction of D-Trp at position 8 improved the activity by 8-fold.
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Rivier; J., Vale; W., et al., Biochem. Biophys. Res. Commun., 1975, 65, 746
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
D-Trp at i+1 position improved the activity
HN
NH
HN
NH
HN
NH
HN
H2NO
O
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
OHO
OSS
NH2H2N
O
NH
NH2
HOHOHO
8
91011
1213
7654
3
14
21
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Veber; D.F, Hirschmann; R., et al., PNAS, 1978, 75, 2636
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Search for active conformation
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
NH2
NH
NH2
HOHO
SS
III, IIa (CysїCys(Acm))VI, V (Cys=Cys(Acm))
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
NH2H2N
O
NH
NH2
HOHOHO
SS
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
NH2
NH
NH2
HOHO
S S
IV, IIb (Cys=Cys(Acm))
8
910
11
12
13
76
5
4
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
NH2H2N
O
NH
NH2
HOHOHO
8
910
11
12
13
76
5
4
Cyclic analog
8
9101112
13
765
4
8
9
10
11
12
13
76
5
4
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Veber; D.F, Hirschmann; R., et al., Nature, 1979, 280, 512
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Extraction of the essential structure
HN
NH
HN
NH
HN
O
O
O
O
O OHN
O
HN
NH
OHN
ONH
OHN
O
NH2
NH
NH2
HOHO
SS
I
8
91011
12
13
76
5
4
HN
NH
HN
O
O
O OHN
O
HN
NH
OHN
O
NH
NH2
HO
SS
III
8
91011
12
76
5
HN
NH
HN
O
O
O OHN
O
HN
NH
OHN
O
NH
NH2
HOIIa
8
91011
76
12
5
lShorter bi-cyclic peptide resulted in ca. 2.5-fold increase in the activity.
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Veber; D.F, Hirschmann; R., et al., Nature, 1981, 292, 55Lewis; I., Bruns; C., et al., J. Med. Chem., 2003, 46, 2334
NH
HN
O
O OHN
O
HN
NH
O
NH
NH2
HO
NO
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
DĂĐƌŽĐLJĐůŝnjĂƚŝŽŶďLJɴ-turn inducing amino acids
8
NH
HN
O
O OHN
O
HN
NH
O
NH
NH2
NO
O NH
H2N
OPasireotide
lIncorporation of turn inducing sequence resulted in improved effect p.o.
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Biron; E., Kessler; H. et al., ACIE, 2008, 47, 2595
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
NH
NO
O ON
O
HN
N
O
NH
NH2
HO
NO
11
67 8
9
10
8
Further improvement by N-Methylation
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 in the loss of bioavailability.
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Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Relation between secondary structure and bioavailability
Biron; E., Kessler; H. et al., ACIE, 2008, 47, 2595
NH
NO
O ON
O
HN
N
O
NH
NH2
HO
NO
Me
Me
Me
11
67 8
9
10
Phe11їD-Phe
Loss of binding affinityLoss of bioavailability
type II’ɴ-turn
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Beck; J.G, Kessler; H., et al., JACS, 2012, 134, 12125Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
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.
lϮŽĨϯďŝŽĂǀĂŝůĂďůĞĂŶĚĐŽŶĨŽƌŵĂƚŝŽŶĂůůLJƵŶŝĨŽƌŵƉĞƉƚŝĚĞƐŚŽǁĞĚɴ//-ɴs/turn structure.
lThe structure is the same as cyclosporin A and the somatostatin analog.
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Beck; J.G, Kessler; H., et al., JACS, 2012, 134, 12125Räder; A.F.B., Kessler; H., et al., Bioorg. Med. Chem., 2018, 26, 2766
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Relation between secondary structure and bioavailability
Shielding of solvateable NH of lipophilic peptide improve permeability
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Rezail; T., Lokey; R.S., et al., JACS, 2006, 128, 2510Marelli; U.K., Kessler; H., et al., Chem. Euro. J., 2015, 21, 8023
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
lBlocking of NH does not generally improve bioavailability.
Turn inducing amino acids
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Non-ProteinogenicProteinogenic
NH
HN
O OHN
O
HN
O
R1R2
R3R4
i+1
i+2i+3
i
DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
NH
HN
O ON
O
HN
O
R1R2
R4
i+1
i+2i+3
i
NH
N
O ON
O
HN
O
R4
i+1
i+2i+3
i
R
NH2
O
H
Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
NH
N
O ON
O
HN
O
R1
R4
i+1
i+2i+3
i
NH
N
O ONH
O
HN
O
R1
R4
i+1
i+2i+3
i
R3
Tendency of turn induced by Pro-Xaa sequence
lInduction of turn can be controlled, and indeed there are some major and strong turn inducer, the structure of turn induced will usually be highly dependent on the context.
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47 DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
Metrano; A.J., Miller; S.J., et al., JACS, 2017, 139, 492
N-Methylation
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48 DŝŵĞƚŝĐƐŽĨƐĞĐŽŶĚĂƌLJƐƚƌƵĐƚƵƌĞɴ-turn
NH
HN
O ON
O
HN
O
R1R2
R4
i+1
i+2i+3
i
NH
HN
O ON
O
HN
O
R1R2
R4
i+1
i+2i+3
i
R
NH
N
O ON
O
HN
O
R1
R4
i+1
i+2i+3
i
NH
N
O ON
O
HN
O
R1R2
R3R4
i+1
i+2i+3
i NH
N
O OHN
O
HN
O
R1R2
R3R4
i+1
i+2i+3
iNH
N
O ON
O
HN
O
R1R2
R4
i+1
i+2i+3
i
lN-Methylation can be seen as a surrogate of proline.
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1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
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 hydrogen bonding, steric shielding)
l Lipophilicity (lipophilic sidechains)l ^ƉĞĐŝĨŝĐĐŽŶĨŽƌŵĂƚŝŽŶ;ĞŐɴ//-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
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54
1. Introduction2. Major secondary structures and its mimetics• ɲ-helix• džĂŵƉůĞŽĨɲ-helix mimetic PPI inhibitor • ɴ-sheet• džĂŵƉůĞŽĨɴ-sheet mimetic PPI inhibitor • Turns• džĂŵƉůĞŽĨɴ-turn mimetics
3. Summary4. Appendix
Synthesis of SAH-p53-x
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55 Appendix
Structure of Enfuvirtide
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56 Appendix
Synthesis Oligo N-substituted Glycine
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57 Appendix
Simon; R.J., Bartlett; P.A., et al., P.N.A.S, 1992, 89, 9367
PyBOP or PyBrop
SPPS
Only example of highly potent inhibitor made of oligo-NSG
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58 Appendix
Zuckermann; R.N., et al., J. Med. Chem., 1994, 37, 2678
ɲ1-adrenergic receptor
ʅ-opiate receptor
Synthesis of Oligo N-substituted Alanine
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59 Appendix
Morimoto; J., Fukuda; Y., Sando; S., et al., J. A. C. S, 2019, 141, 14612
Other foldamers
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60 Appendix
Gangloff; N, Luxenhofer; R., et al., Chem. Rev., 2016, 116, 1753
C,D-ƚLJƉĞŵŝŵĞƚŝĐƐŽĨɲ-helixAppendix
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Pelay-Gimeno; M, et al., ACIE, 2015, 54, 8896
C,D-ƚLJƉĞŵŝŵĞƚŝĐƐŽĨɲ-helixAppendix
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ƉƉĞŶĚŝdžWŽƉƵůĂƚŝŽŶŽĨɴ-turns
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63 Appendix
Bravern; A.G., Sci. Rep., 2016, 6, 33191
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