Furan-based locked Z -vinylogous γ-amino acid stabilizing protein α-turn in water-soluble cyclic α3γ tetrapeptides

Article abstract of DOI:10.1021/ol5002126

Described here is the design, synthesis, and conformational analysis of cyclic tetrapeptides (CTPs) with α₃γ architecture containing a furan-based locked Z-vinylogous amino acid (Vaa). This unnatural amino acid locks into a γ-turn that induces

Full text of DOI:10.1021/ol5002126

Letter
pubs.acs.org/OrgLett
Furan-Based Locked Z‑Vinylogous γ‑Amino Acid Stabilizing Protein
α‑Turn in Water-Soluble Cyclic α3γ Tetrapeptides
Yarkali Krishna,†,§ Shrikant Sharma,‡,§ Ravi S. Ampapathi,*,‡ and Dipankar Koley*,†
‡
†Medicinal and Process Chemistry Division and Centre for Nuclear Magnetic Resonance, SAIF, CSIR-Central Drug Research
Institute, Lucknow, Uttar Pradesh 226031, India
S
* Supporting Information
ABSTRACT: Described here is the design, synthesis, and
conformational analysis of cyclic tetrapeptides (CTPs) with
α3γ architecture containing a furan-based locked Z-vinylogous
amino acid (Vaa). This unnatural amino acid locks into a γ-
turn that induces type IαRS-turn in the CTPs. Stabilized by a
13-membered intramolecular H-bond, these CTPs show
robust conformation in water and aprotic solvent irrespective
of the sequence of tripeptide consisting of α-amino acids used.
urns play an important structural role in the stability of
globular proteins and, being exposed on the protein
(i)CO and (i+4)NH, forming a 13-membered pseudocycle.
Interestingly, while consecutive linking of α-turn with identical
backbone dihedral angles (ϕ −58°, ψ −47°) among all the
residues leads to the formation of α-helix,7 α-turns in proteins
(tight α-turn4c) do not follow this rule and frequently change
the backbone dihedral angles, helical pitch, and orientation of
the side chains (Figure 1B).4a Nine different types of tight α-
turn have been identified on the basis of varying backbone
dihedral angles, and type I-αRS is the most widely occurring
(238 occurrences out of 356 α-turns in 190 proteins).4b,c
Surprisingly, while numerous reports have been described to
mimic α-helices,8−12 reports to stabilize protein α-turn using
small molecules are rare. There are few approaches to stabilize
single α-turn, although only for α-turn of an α-helix.13 Very
recently, Fairlie et al. reported14 cyclic peptides that mimic tight
α-turns. However, the side chain has been engaged in those
peptides to stabilize the motifs.
T
surfaces, often involve in a variety of molecular recognition
processes.1,2 Approximately, more than one hundred G-protein
coupled receptors (GPCRs) have been identified that recognize
ligand with turn structure.2 Consequently, development of turn
mimetics as the modulators of protein−protein interactions has
become an attractive approach in drug discovery.2,3 Depending
on the number of residues involved, turns are classified4 as δ-,
γ-, β-, α-, and π- turns (Figure 1A), and among these, γ- and β-
As part of our ongoing program on peptidomimetics,15 we
desired to use a furan-based Z-vinylogous γ-amino acid (Vaa) as
the general template (surrogate of the terminal residues of a
tight α-turn) in which a tripeptide will be grafted without
disturbing its side chains and the template would preorganize
the resultant cyclic tetrapeptide (CTP) into a stable
conformation irrespective of the sequence used (Figure 1C).
The rationalities for choosing Vaa are as follows: (1) the furan
scaffold of Vaa would bring conformational rigidity in the CTP
by locking the cis geometry in 2; (2) an intraresidual 7-
membered H-bond in the Vaa (as predicted theoretically by
Hoffmann et al.16) would eventually replicate the (i,i+4) 13-
membered H-bonding feature of α-turn; (3) the flat Vaa
scaffold would not allow the peptide to maintain the pitch
corresponding to the α-turn of an α-helix; (4) the resultant 14-
membered cyclic ring would be released from the strain of a 12-
Figure 1. (A) Various tight turn motifs. (B) Schematic diagram of α-
turn with variable dihedral angles of inner three residues.4a,14 (C) Vaa
as the surrogate of i and i+4 residues.
turns are very well explored.2,5 α-Turn, one of the important
turn motifs, occurs at many key sites (enzyme active site, metal
binding domains, kinks of helices, etc.) of proteins like human
lysozyme, glyceraldehydes-3 phosphate dehydrogenase, ferre-
doxin I, T-cell surface of glycoprotein, azurine, HIV gp120, p-
hydroxybenzoate hydroxylate, glutathione peroxidase, etc.4c,6
Structurally, α-turn involves five amino acid residues where the
inner three-residue segment is stabilized by a H-bond between
Received: January 21, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
membered classical α4 CTP, and it would also circumvent the
associated limitations of classical α4 CTP, i.e., conformational
heterogeneity, metabolic instability;17 (5) the integrated
additional carboxylic acid could be used for any postcyclization
modification. Herein, we describe synthesis and conformational
analysis of water-stable highly robust CTPs with α3γ
architecture (Scheme 1).
Scheme 2. Synthesis of Cyclic Peptidomimetics
Scheme 1. Vinylogous Amino Acid-Based CTPs
a
Reagents and conditions: (a) (i) NaIO4, MeOH:H2O (1:1), 0 °C to
rt, 3 h, (ii) NaClO2, NaH2PO4, H2O2, CH3CN, 0 °C to rt, 3 h, (iii)
CH2N2, diethyl ether, 75% over three steps; (b) (i) NBS, AIBN, CCl4,
reflux, 2 h, (ii) NaN3, DMF, 65 °C, 30 min, 68% over two steps; (c)
H2, Pd/C, ethyl acetate, quantitative; (d) 6a/6b/6c/6d, 1-hydrox-
ybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (EDCI), diisopropylethylamine
(DIPEA), DCM, then 2, 0 °C to rt, 8 h, 75−85%; (e) (i) TFA:DCM
(1:1), 0 °C to rt, 3 h, (ii) FDPP, DIPEA, CH3CN, −5 °C to rt, 60−72
h, 52−60%; (f) (i) LiOH, THF:MeOH:H2O, (ii) HOBt, EDCI, DCM,
RCH2CH2NH2, DIPEA, 71−79%; (g) H2, Pd/C, MeOH, quantitative;
(h) (i) TFA:DCM (1:1), 0 °C to rt, 1 h, quantitative; 6a = Boc-Val-
Ala-Phe-OH; 6b = Boc-Phe-Phe-Leu-OH; 6a = Boc-Ala-Ala-Phe-OH;
6b = Boc-Phe-Phe-Ala-OH.
Syntheses of 2 and CTPs are described in Scheme 2. The
vicinal 1,2 diol of 318 was oxidatively cleaved to furnish
aldehyde, which was oxidized to carboxylic acid and esterified as
methyl ester 4 using diazomethane in 75% yield over three
steps. Allylic bromination of 4 using N-bromo succinimide
followed by azidation by NaN3 under heating condition
delivered azido diester 5 in 68% overall yield. The furan
amino ester derivative 2 was obtained in a quantitative yield
from 5 upon catalytic hydrogenation and coupled with the
carboxylic acids derivatives 6a−d using EDCI and HOBt as
coupling reagent in dichloromethane to furnish the linear
tetrapeptides 7a−d in 75−85% overall yield. TFA-mediated
one-pot deprotection of tert-butyl ester and Boc in DCM from
7a−d followed by intramolecular cyclization in acetonitrile
using pentafluorophenyl diphenylphosphinate (FDPP)/DIPEA
under dilute condition (0.5 × 10−2 M) furnished the CTPs 8a−
d, having α3γ architecture in 52−60% overall yield. To
determine the conformational preferences of the CTPs in
nonaqueous and aqueous medium various hydrophobic and
hydrophilic side chains were attached to synthesize 1aA−dD.
In CD spectroscopy, the electronic transition of the
backbone amide of a peptide is expected to occur in the far-
UV region, and delightfully, the CD spectra of 1aB−1dB
showed absorption maxima at 222 and 208 nm and a large
minimum at 195 nm, characteristic of a helical conformation.19
In addition, the absorption minimum observed at 258 nm
(near-UV region) is possibly due to the electronic transition of
the aromatic groups (furan and phenyl).20
of predominant well-defined folded structures in aqueous and
aprotic (DMSO-d6) solvents.20 Variable-temperature (VT) H
1
NMR spectra of water-soluble CTPs (1aD, 1bD, 1cD, 1dD)
showed small changes in the amide NH chemical shift of Vaa
(ΔδNH/T −4.3 ppb/°C in 1dD) and large changes that of other
amide protons (ΔδNH/T −7.1, −6.7, and −6.4 ppb/°C for
1Phe, 2Phe, 3Ala, respectively, in 1dD), indicating the
20,21
4
involvement of VaaNH in the H-bonding (Figure 2A).
Further the invariance of the amide NH chemical shifts
observed in the concentration-dependent-aggregation studies
4
clearly suggested the participation of VaaNH in the intra-
molecular H-bonding (Figure 2B).16 Additional support for the
intramolecular H-bonding of VaaNH appeared from hydrogen/
1
deuterium exchange experiment. H NMR spectra of 1dD in
Encouraged by the characteristic CD spectrum of a helical
peptide, we analyzed the conformational preferences of the
CTPs using NMR spectroscopic techniques. Sharp and well
resolved amide NH signals of the CTPs suggested the presence
Figure 2. VT and concentration-dependent-aggregation studies. (A)
VT 1H NMR spectra of amide protons of 1dD in H2O:D2O (9:1). (B)
Concentration independence of amide proton chemical shifts of 1dD
in H2O:D2O (9:1).
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Letter
4
H2O:D2O (5:1) showed a slower rate of exchange of VaaNH
1
3
and 2PheNH than the PheNH, AlaNH, and side chain amide
protons.20
Being short peptide, the characteristic NOE correlations of
an α-helical peptide [e.g., (i)CαH ↔ (i+3)NH, (i)CαH ↔ (i
+4)NH] were absent. However, characteristic NOEs observed
in the ROESY spectra of these CTPs between VaaNH ↔ (i
+3)VaaNH, VaaNH ↔ (i+2)VaaNH, and (i+1)VaaNH ↔ (i
+2)VaaNH suggested the close proximity of the amide protons
in the preferred single conformation (Figure 3A). Absence of
Figure 4. Structure ensemble of CTPs in H2O:D2O (9:1) super-
imposed 20 lowest energy structures of 1aD (I), 1bD (II), 1cD (III),
and 1dD (IV). The H-bond is shown as dotted lines, and for clarity all
protons are removed except for amides.
Figure 3. (A) ROESY spectrum of 1dD in H2O:D2O (9:1) where
NOEs between 1PheNH ↔ 2PheNH, 2PheNH ↔ 3AlaNH, 3AlaNH ↔
4VaaNH, and 4VaaNH ↔ 2PheNH are marked as 1, 2, 3, and 4,
respectively. (B) Comparison of δ(CαH) region of cyclic peptide (8d)
and linear peptide (7d).
VaaNH (i+4), characteristic of a tight α-turn. Further, the ϕ
values calculated from the CTPs fit very well with the region
defined by Ramachandran plot of the type I-αRS found in
proteins and previously described by Chou et al.4c
In aprotic solvent, these CTPs displayed almost identical
coupling constant values, NOE correlations. However, the VT
studies15 revealed that both VaaNH and (i+2)VaaNH were H-
bonded. The 20 lowest energy structures of 1aB−1dB are
superimposed and presented in Figure 5. This suggested that all
NOE between any two consecutive CαH protons suggested the
nonexistence of cis-amide bond. Importantly, the δ(CαH) of all
the residues in CTPs displayed an upfield chemical shift (0.08,
1
2
3
0.11, and 0.24 ppm for Phe, Phe, and Ala, respectively, in
8D) relative to the corresponding residues in linear peptides,
thus supporting the fact that these CTPs folded into helical
conformation (Figure 3B).22
3
The JNH‑CαH values of (i+1)Vaa, (i+2)Vaa, and (i+3)Vaa
residues (∼4.5, ∼9.0, and ∼8.0 Hz, respectively) of the water-
1
soluble CTPs obtained from the H NMR spectra suggested
that the CTPs have nonidentical backbone dihedral angles (ϕ)
(Table 1), which implied that the CTPs do not adopt the α-
Table 1. Dihedral Angles of (i+1)Vaa, (i+2)Vaa, (i+3)Vaa
3
Calculated from JNH‑CαH Values
d(Å)
d(Å)
C(i)−
O(i)−
CTP
ϕ(i+1)
ϕ(i+2)
−115
−110 10
−110 10
ϕ(i+3)
C(i+3) N(i+4)
1aD
1bD
1cD
1dD
−60
−65
−65
−55
5
5
−110
−110
5
5
4.88
4.94
4.84
4.94
2.88
2.86
2.89
2.90
5
5
5
Figure 5. Structure ensemble of CTPs in DMSO-d6. Superimposed 20
lowest energy structures of 1aB (I), 1bB (II), 1cB (III) and 1dB (IV).
The H-bond is shown as dotted lines, and for clarity all protons are
removed except for amides.
−105 10
−100 10
−100
5
turn conformation of an α-helix. On the other hand, the ϕ(i+1)
values of all the CTPs lie within the α-helical region of the
Ramachandran plot.14,23 Solution structural calculations of
these CTPs were carried out using the ROESY spectral data
acquired in H2O:D2O (9:1) at 300 K. Both distance and
torsional angle values were applied as constraints in the
restrained molecular dynamics (MD) studies and carried out in
Accelrys Discover studio (3.0) using CHARMm force field.24
The 20 lowest energy structures of 1(a−d)D are superimposed,
and the ensemble is presented in Figure 4. These 20 structures
converged very well, suggesting the rigidity in their conforma-
the CTPs possess similar type of secondary structure as
observed in aqueous solution. However, an additional H
bonding between (i)CO and (i+2)NH was also observed,
leading to a reverse γ-turn structure.
In conclusion, reconstruction of protein α-turn was
accomplished using small molecule-based peptidomimetic.
The template Vaa with its rigid frame and intraresidual H-
bonding propensity dictated the CTP to mimic the most widely
occurring tight α-turn of type I-αRS. Importantly, the structure
is stable in both aqueous and aprotic solvents and does not
depend on the sequence of inner three residues, which implied
that the stability of the secondary structure is governed by the
template of Vaa. Consequently, the liberty to alter the side-
chains of the amino acids and scope to introduce a variety of
1
tional preferences. Therefore, considering the CD and VT H
NMR spectroscopic properties, distance between O(i)−N(i+4)
(<3.5 Å) and (ϕ) values, it is suggested that the CTPs are
stabilized by a 13-membered H-bond between VaaCO (i) and
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data of
all new compounds, 2D-ROESY spectra for the cyclic
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ravi_sa@cdri.res.in.
*E-mail: dkoley@cdri.res.in.
Author Contributions
§Y. Krishna and S. Sharma contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by CSIR-New Delhi (as part of the
XII Five Year plan program under Biodiscovery-BSC0120). We
thank reviewers for their critical comments and valuable
suggestions and SAIF division, CSIR-CDRI for the analytical
facilities. Y.K. and S.S. thank CSIR-New Delhi for the award of
Senior Research Fellowship. This is CDRI communication No.
8641.
(14) Hoang, H. N.; Driver, R. W.; Beyer, R. L.; Malde, A. K.; Le, G.
T.; Abbenante, G.; Mark, A. E.; Fairlie, D. P. Angew. Chem., Int. Ed.
2011, 50, 11107.
(15) (a) Sharma, A.; Sharma, S.; Tripathi, R. P.; Ampapathi, R. S. J.
Org. Chem. 2012, 77, 2001. (b) Chakraborty, T. K.; Koley, D.; Ravi, R.;
Kunwar, A. C. Org. Biomol. Chem. 2007, 5, 3713.
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