Dipeptide and Synthetic Oligomers Journal Summary

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DOI: 10.1002/chem.201502690
& Peptidomimetics
Hybrid Diphenylalkyne–Dipeptide Oligomers Induce Multistrand
b-Sheet Formation
Jonathan E. Ross, Peter C. Knipe, Sam Thompson,* and Andrew D. Hamilton*[a]
Dedicated to Professor Sir Alan R. Battersby FRS on the occasion of his 90th birthday
Abstract: Functionalized diphenylalkynes provide a template for the presentation of protein-like surfaces composed of multistrand b-sheets. The conformational properties of three-, four-, and seven-stranded systems have
been investigated in the solid- and solution-state. This
class of molecule may be suitable for the mediation of
therapeutically relevant protein–protein interactions.
There is much current interest in the design of synthetic oligomers that mimic the recognition and folding properties of secondary structural domains on the surface of proteins.[1] These
foldamers[2] have the potential to bind complementary protein
targets and modulate their interactions with other proteins.[3]
Considerable progress has been made in the design of various
unnatural amino acid oligomers that are controlled by intramolecular hydrogen-bonding interactions. In particular, b-peptides,[4, 5] g-peptides,[6] and sequences containing aminoquinolines,[7] anthranilamides,[8, 9] and dialkylamino acids[10–14] have
been shown to adopt helical conformations of varying pitch
and dimensions. The b-sheet is also an important secondary
structural protein element, motivating researchers to develop
a range of synthetic templation strategies for two-stranded
systems.[12–18] Macrocyclic peptides have frequently been used
to stabilize the formation of sheetlike structures and have provided insights into their supramolecular properties.[19] However,
there are a limited number of templates that take advantage
of intramolecular hydrogen bonding to stabilize structures
formed of three or more strands.[20] These include turn mimics
that incorporate d-Pro,[21, 22] oligomers of a/b-amino acids,[23, 24]
and the self-assembly of two-stranded b-sheet mimics[25] and
macrocycles[26, 27] into larger complexes.
Nature provides many examples of extended and stable
sheet structures, as both components of soluble globular proteins and insoluble aggregates such as amyloid fibrils. These
provide two functionalized surfaces, formed from the side[a] J. E. Ross, Dr. P. C. Knipe, Dr. S. Thompson, Prof. Dr. A. D. Hamilton
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: sam.thompson@chem.ox.ac.uk
Homepage: http://hamilton.chem.ox.ac.uk
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 13518 – 13521
Figure 1. Multistranded b-sheets are key components of higher-order protein structures, and present large surface areas for interfacial protein–protein
interactions: a) the b-repeat (also known as a b-meander), exemplified by
Koide’s protein self-assembly mimics (PDB 2HKD);[29] b) extended b-meander
motifs based upon the diphenylalkyne linker as a turn motif.
chain residues projected above and below the folded frame.
The b-meander protein is an example of a super-secondary
protein element formed of several short peptide strands occupying extended conformations, and is itself a common component of larger structures such as the b-barrel (Figure 1 A).[28]
Our interest lay in creating oligomeric scaffolds that stabilize
extended b-sheet-like structures, with programmable surfaces
projected above and below a common plane. Di-functionalized
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
diphenylalkynes were introduced by Kemp as a non-peptidic
anti-parallel b-turn inducer,[30, 31] and have been extended by
Spivey to display peptide loops,[32, 33] and by our group to template bi-directional b-sheet formation.[34] The motif also has the
potential to stabilize large surfaces as a modular unit of a foldamer, in which multiple peptide strands are linked in an antiparallel fashion (Figure 1 B).
To explore the folding propensities of a series of anti-parallel
two-peptide strands linked through diphenylalkynes, we synthesized 1 on a multigram scale from readily available starting
materials (see the Supporting information). Alanine was selected as the amino acid for this proof-of-principle system due to
its propensity to form b-sheets. Building block 1 can be orthogonally deprotected to reveal either the free C-terminus 2,
or N-terminus 3. Amide coupling between 2 and 3 gave
double turn motif 4 (Scheme 1). Further elaboration through
iterative deprotection, amidation with a suitable two-amino
acid unit (2 or 3), and capping of the resultant termini with
protected amino acids gave three- (5) and four-stranded (6)
mimics (Figure 2).
Scheme 1. Synthesis of a double turn motif with orthogonal N-/C-terminal
protecting groups. Conditions: a) trifluoroacetic acid, CH2Cl2, 93 %, b) piperidine:CH2Cl2 (0.1 m, 4:1 v/v), 95 %; c) EDC, HOBt, iPr2NEt, CH2Cl2, 62 %. Dashed
lines indicate hydrogen bonds. EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt = hydroxybenzotriazole.
Extensive cross-strand correlations between the Ca-, Cb-,
and amide N-Hs of the ROESY (5) and NOESY (6) CDCl3 spectra
were consistent with the population of folded multistrand
sheet conformations.[35, 36] Support for the existence of wellconserved intramolecular hydrogen-bond networks is provided
by N-H/D exchange between a solution of mimic in a mixture
of CDCl3 and CD3OD, where hydrogen-bonded NHs that are
protected from the solvent are expected to undergo exchange
less rapidly than those exposed to solvent.[34, 37] All NHs of
single-stranded control molecules 8–10 underwent greater
than 50 % exchange after 9 min. Likewise, 50 % exchange occurred for Hb/Hg (three-stranded 5) and Hb/Hj (four-stranded 6)
in less than 5 min, suggesting that they occupy solvent exposed positions. Hc/Hf (of 5 and 6), and Hi (of 6), closest to the
turn motifs, showed very slow rates with less than 12 % exchange after 105 min. Ha (of 5), Hd/He (of 5 and 6), and Hg/Hh
(of 6), show intermediate rates of exchange, indicative of hydrogen bonds further from the turn motifs being of moderate
strength. Consistent with the ROESY data, Hh (of 5), and Hk (of
6) reached 50 % exchange within five minutes. It may be that
the additional length of the N- compared to the C-terminal
Chem. Eur. J. 2015, 21, 13518 – 13521
Figure 2. Solution-phase analysis of meander mimics: a) ROESY of threestranded 5; and b) NOESY of four-stranded 6; c) single-stranded control
compounds 8, 9, and 10, which are incapable of intramolecular sheet formation. Solid and dashed red arrows indicate selected strong and weak nOe
correlations respectively (13.33 mm in CDCl3).
strand results in a steric clash between the tert-butyl group
and the aromatic hydrogens, thus weakening the hydrogen
bonding and causing fraying. Alternatively, weaker H-bonding
at this position may be due to the reduced H-bond donor ability of carbamate, relative to amide, NHs (labeling of NHs is
shown in Figure 2, full data in the Supporting Information).
The Ca-Hs of mimics 5 and 6 show a pronounced downfield
shift in the 1H NMR spectra when compared to single-stranded
control molecules, consistent with increasing b-sheet character.[38, 39] The non-terminal amino acids showed shifts of 0.78–
1.04 (5) and 0.81–1.21 ppm (6) relative to the controls. Larger
values in the latter case are likely due to the enforcement of
greater sheet character by increased interstrand H-bond cooperativity. The corresponding range for terminal amino acids
was 0.12–0.32 ppm, indicative of less-pronounced b-sheet
structure (Figure 3 a). The assignment of a secondary structural
propensity score using the Foreman–Kay method[40] allows
contributions from different nuclei to be weighted according
to their sensitivity to a- and b-structure. Mean b-sheet scores
in excess of 94.0 and 99.8 % for three- (5) and four-stranded
mimics (6), respectively, were consistent with significant bsheet character, whilst control molecules 8–10 showed minimal b-sheet propensity (between 0 and 31.7 %).
Solution-phase conformational behavior in a more demanding medium for intramolecular H-bonding was explored by titration of (CD3)2SO into a solution of sheet-mimic in CDCl3.
Hb/Hg (of 5) and Hb/Hj (of 6) shifted markedly downfield, suggesting greater exposure to solvent, whereas the other hydrogens shifted to an equal or greater degree upfield, consistent
with adoption of a well-folded multi-strand sheet conformation
(Figure 3 b).[41] For mimics 5 and 6 a quantitative comparison
of 1H NMR chemical shifts of the non-terminal amide NHs for
spectra acquired in neat CDCl3 and neat (CD3)2SO gave a high
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 3. a) Secondary structural behavior: 1H NMR chemical-shift values of
the a-hydrogens in i) three-stranded 5; and ii) four-stranded 6 mimics relative to single-stranded controls (8–10). Residue numbering indicated in
Figure 2. b) Amide 1H NMR behavior upon titration of (CD3)2SO into a CDCl3
solution of i) three-stranded 5 and ii) four-stranded 6 mimics. Labeling of
NHs indicated in Figure 2. 10 mm in 500 mL of CDCl3 ; (CD3)2SO added in portions as follows: 10, 20, 20, 50, 50, 50 mL.
level of confidence for hydrogen-bonding networks consistent
with well-folded multi-strand sheet conformation.[42] The hydrogens corresponding to the C- and N-terminal amino acids
(He/Hh for 5, He/Hk for 6) gave intermediate values indicative of
fraying, whereas the chemical shift change of the external hy-
drogens (Hb/Hg for 5, Hb/Hj for 6) suggested an absence of intramolecular H-bonding.[43]
X-ray crystallography of single crystals of 5 was consistent
with a structure formed of three intramolecularly hydrogenbonded strands. In agreement with the solution-phase work,
a network of six intramolecular hydrogen bonds places three
side-chains above the plane and three below (coloured orange
and purple respectively, Figure 4 a/b).[44] Average dihedral
angles of (f, Y) = (¢135 œ 328, 136 œ 378) are in excellent
agreement with those of a canonical b-sheet (¢135, 135). See
the Supporting Information for more details.[45]
With solid- and solution-phase data consistent with the
three- and four-stranded mimics adopting multi-stranded bsheet conformation, we sought to explore the preparation of
extended systems with a greater number of strands. Further
iteration of the synthetic route afforded seven-stranded meander mimic 7, with protected termini allowing extension to
larger surfaces (Figure 4 c,d).[36]
Circular dichroism spectra of three- (5), four- (6), and sevenstranded mini-protein mimic (7) showed maxima at 253 nm
and minima at 228 nm, consistent with b-sheet formation,
whereas single-stranded control (9) gave a spectrum characteristic of random coil behavior. Maxima at 255 nm are due to
chiral perturbations of the 2-amino-2’-diphenylalkyne chromophore (Figure 4 e).[30, 31]
In conclusion, we have shown that several short peptide
strands may be linked in an anti-parallel arrangement by diphenylalkynes to give large surfaces presenting side-chains on
two faces. The approach provides a template for the stabilization of multi-strand b-sheets and may find use in mediating
protein–protein interactions. Work is underway to prepare extended systems containing longer sequences of amino acids
per strand, and to incorporate hydrophilic side chains for functional studies in aqueous media.
Figure 4. X-ray diffraction structure of three-stranded mimic 5: a) top- and b) side-elevation. Side-chains highlighted in orange and purple (opposite face), diphenylalkyne turns in maroon, tert-butyl protecting groups in grey, dotted red lines represent hydrogen bonds, some hydrogens omitted for clarity. Mimicry
of a seven-stranded b-meander 7: c) structure; d) schematic representation; e) circular dichroism mean residue ellipticity ([q]) of three- (5), four- (6), and
seven-stranded (7) mimics relative to single-stranded control molecule (9); averages of ten acquisitions, 100 mm in trifluoroethanol.
Chem. Eur. J. 2015, 21, 13518 – 13521
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
We thank The EPSRC (EP/G03706X/1) and the University of
Oxford for funding and Diamond Light Source for an award of
beam time (MT9981).
Keywords: foldamer · peptidomimetics · protein surface ·
protein–protein interaction · secondary structure · b-sheet
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Received: July 9, 2015
Published online on August 11, 2015
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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