Aromatic Foldamer Helices as α-Helix Extended Surface Mimetics

Article abstract of DOI:10.1002/chem.202004064

Helically folded aromatic oligoamide foldamers have a size and geometrical parameters very distinct from those of α-helices and are not obvious candidates for α-helix mimicry. Nevertheless, they offer multiple sites for attaching side chains. It was found that some arrays of side chains at the surface of an aromatic helix make it possible to mimic extended α-helical surfaces. Synthetic methods were developed to produce quinoline monomers suitably functionalized for solid phase synthesis. A dodecamer was prepared. Its crystal structure validated the initial design and showed helix bundling involving the α-helix-like interface. These results open up new uses of aromatic helices to recognize protein surfaces and to program helix bundling in water.

Full text of DOI:10.1002/chem.202004064

Accepted Article
Accepted Article
Title: Aromatic foldamer helices as α-helix extended surface mimetics
Authors: Ivan Huc, Márton Zwillinger, Post Sai Reddy, Barbara Wicher,
Pradeep K. Mandal, Marton Csekei, Lucile Fischer, and
András Kotschy
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202004064
Link to VoR: https://doi.org/10.1002/chem.202004064
01/2020

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Aromatic foldamer helices as -helix extended surface mimetics
Márton Zwillinger,[a] Post Sai Reddy,[b,c] Barbara Wicher,[d] Pradeep K. Mandal,[c] Marton Csekei,[a]
Lucile Fischer,[b] András Kotschy*[a] and Ivan Huc*[c]
[a]
M. Zwillinger, Dr. M. Csekei, Dr. A. Kotschy
Servier Research Institute of Medicinal Chemistry
Záhony utca 7. Budapest, 1031, Hungary.
E-mail: andras.kotschy@servier.com
[b]
[c]
Dr. P. Sai Reddy, Dr. L. Fischer
Université de Bordeaux, CNRS, Bordeaux Institut National Polytechnique, CBMN (UMR 5248), IECB
2 rue Robert Escarpit, 33600 Pessac, France.
Dr. P. Sai Reddy, Dr. P. K. Mandal, Prof. Dr. I. Huc
Department of Pharmacy and Center for Integrated Protein Science
Ludwig-Maximilians-Universität,
Butenandtstr. 5-13, 81377 München, Germany.
E-mail: ivan.huc@cup.lmu.de
URL: https://huc.cup.uni-muenchen.de/
[d]
Dr. B. Wicher
Department of Chemical Technology of Drugs
Poznan University of Medical Sciences
Grunwaldzka 6, 60–780 Poznan, Poland
Supporting information for this article is given via a link at the end of the document.
Abstract: Helically folded aromatic oligoamide foldamers have a size
and geometrical parameters very distinct from those of -helices and
are not obvious candidates for -helix mimicry. Nevertheless, they
offer multiple sites for attaching side chains. We found that some
arrays of side chains at the surface of an aromatic helix make it
possible to mimic extended -helical surfaces. Synthetic methods
were developed to produce quinoline monomers suitably
functionalized for solid phase synthesis. A dodecamer was prepared.
Its crystal structure validated the initial design and showed helix
bundling involving the -helix-like interface. These results open up
new uses of aromatic helices to recognize protein surfaces and to
program helix bundling in water.
Foldamers with aryl rings in their main chains may adopt
stable helical conformations in solution.[12] These helices feature
a pitch of 3.5 Å and a diameter of at least 1.3 nm that do not relate
to those of an -helix. They can be decorated with proteinogenic
side chains and may interact with protein surfaces[13] but, at first
sight, they appear to be unsuitable for -helix mimicry (see Fig. 1
in ref 14). Instead, some have been used as duplex B-DNA
charge surface mimetics.[15] Nevertheless, aromatic foldamers
possess many sites for functionalization and thus for creating
diverse side chain patterns.
Oligoamides of -peptidic 8-amino-2-quinolinecarboxylic
acid Q adopt helical conformations with 2.5 units per turn (Fig.
1a,b).[16] Qn helices have until now been built with low side chain
density, mainly in position 4,[13,14,16] occasionally in position 5,[15,17]
and not in position 6. Upon careful examination of the Qn helix
(Fig. S1), we realized that a simple side chain arrangement
involving 4- and 6-functionalized quinoline rings potentially
matches with that of the face of an -helix. The actual curvature
of -helices may vary between the ideal 3.6613 -helix, with 3
turns for 11 residues (Fig. 1d), and the more classical 3.613 -helix
with 5 turns for 18 units (Fig. 1e, Fig. S2).[18] We found that one
can match four side chains (i, i+3, i+4, i+7) of a 3.613 -helix and
four residues on a P-helical aromatic backbone with an RMSD of
0.7-0.9 Å (Fig. 1e), which fares well compared to reported
values.[8e] The match can be extended to eight side chains (the
above plus i+11, i+14, i+15, i+18) – an entire face – of an
octadecapeptide (Fig. S2). Of note, side chains on the -helix face
that are consecutive in the peptide sequence are matched by
residues separated by two units in the quinoline helix. For a 3.6613
-helix, eight side chains may be matched as well (Fig. 1b-d) but,
due to the difference in curvature, the peptide side chains involved
are not all the same (for the last four: i+8, i+11, i+12, i+15). In the
case of eight side chains, the match shows imperfections (RMSD
of 1.5 Å) but these may be acceptable in so far that not all side
chains may be required, and also that structural parameters may
vary in both quinoline helices and -helices through induced fit.
Additionally, reverting helix N- to C- polarity, inverting
Protein-protein interactions (PPIs) often involve -helices as key,
if not the only, components of the binding interface.[1] Great effort
has thus been devoted to develop -helix mimetics as PPI
competitive inhibitors[2] all the way to the clinic.[3] This includes
methods to enhance -helix conformational stability through
macrocycles involving main chain or side chain functionalities;[3,4]
the use of conformational templates and helix stabilizing
monomers;[5] or the design of peptidic analogues or homologues
that adopt helical conformations more stable than -helices of
similar length.[6] In those cases, side chains may be displayed on
all faces of the helix. In contrast, other -helix mimetics consist of
more or less rigid linear scaffolds, e.g. terphenyl,[7] aromatic
amides,[8] oxopiperazines,[9] pyrrolinone–pyrrolidine,[10] carrying
proteinogenic side chains at distance intervals similar to those of
an -helix, typically following the i, i+4, i+7 arrangement. The
functionalization of these scaffolds on opposite edges to include
other side chain positions has also been proposed.[11] All these
mimics have distinct degrees of freedom and may not perfectly
reproduce a desired side chain arrangement, yet they represent
good starting points for rational design. Here, we introduce the
concept that helical aromatic foldamers may provide original
solutions to -helix mimicry, even in the case of long helices.
1
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handedness, or both, offer slight variations of side chain positions
(e.g. swap 4- and 6-substituents) and enhance the possibility to
find a suitable match (Fig. S3). For example, slightly decreasing
helix curvature may reduce or increase the distance between side
chains within the array depending on the side chains concerned,
but this effect is reversed when inverting helix handedness (note
that the handedness of long aromatic helices in water is kinetically
inert). Furthermore, side chain match may be improved by shifting
some of them to position 5 of the quinoline ring (Fig. S4). Of
course aromatic helices remain much larger than an -helix and
may not fit in a narrow protein groove. But PPIs mediated by a
single -helix face represent the most frequent scenario,[1] and an
aromatic helix would fit in such cases. In addition, aromatic
helices possess other useful features such as resistance to
proteolytic degradation and cell penetration capabilities.[14,19]
Scheme 1. General synthetic strategy of 6-substituted quinoline amino acid
building blocks 1a-h with protected proteinogenic side chains suitable for solid
phase foldamer synthesis (SFPS). 9-BBN: 9-borabicyclo[3.3.1]nonane.
Figure 1. a) Some previously described 4-substituted QXxx monomers and some
of the new 6-substituted Q6Xxx monomers reported in this study. b) Molecular
model and helical wheel of a (Q6XxxQQXxxQ2)3Q6XxxQQXxx octadeca-arylamide
helix showing substituents in position 6 and 4 as blue and green balls,
respectively. c) Structure of an ideal (computed) 3.6613 -helical
hexadecapeptide with -carbons shown as red spheres. d) Overlay of the side
chains in b) and c) with an RMSD of 1.50 Å (see Fig. S2). e) Overlay of four side
chains of Q6XxxQQXxxQ2Q6XxxQQXxx (same color code as b) with four side chains
of a short 3.6 helix (red spheres). Note the position of the side chains in the
3.6 helix slightly differ from those of the 3.66 helix above. An RMSD of 0.92 Å
is calculated if the overlay concerns the peptide -carbon and a quinoline
exocyclic carbon in position 4 or 6 (shown). An RMSD of 0.79 Å is calculated if
the overlay concerns the peptide -carbon and the quinoline endocyclic carbon
in position 4 or 6 (not shown).
To exploit the new design, we first needed a robust synthetic
route to 6-functionalized monomers suitably protected for solid
phase synthesis. The eight monomers 1a-h shown in Scheme 1
were targeted, which bear protected hydrophobic, polar neutral
and cationic side chains. The synthetic route relies on key
intermediates 2 and 3, which were obtained on a multi gram scale.
Compound 2 was prepared in three steps from commercially
available 4-bromo-2-nitro-aniline (see Supporting information)
and 3 in two steps from 2. These initial steps were all
chromatography-free and scalable. Both 2 and 3 bear different
halogen atoms at C-4 and C-6. Selective functionalization at C-6
2
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was achieved, but this route also makes it possible to further
functionalize position 4 if additional side chains are required, that
is, in both positions 4 and 6 of the same quinoline ring. Depending
on the nature of the side chain and availability of the
corresponding synthons, regioselective reactions at C-6 involved
sp2-sp2 (Suzuki), sp2-sp3 (Suzuki) or sp2-sp (Sonogashira) cross-
couplings. Side chains could thus be introduced having a C-C
triple, C-C double or C-C single bond. We therefore had the
choice of a wide range of potential coupling conditions. The loop
through trifluoroacetamido intermediate 3 was required because
the nitro function was found to be incompatible with certain sp2-
sp3 Suzuki couplings. For that, the nitro group was carefully
reduced over Raney-Ni without dehalogenation prior to
trifluoroacetylation.
With commercial or easily available alkyne precursors,
Sonogashira couplings were first attempted. Conditions,
particularly the temperature, were optimized for each coupling to
enhance regioselectivity. While 4a-d were obtained in satisfactory
yields, it was not the case with benzylacetylene. Instead, the
phenylpropenyl side chain of 4e was introduced in fair yield
through an sp2-sp2 Suzuki coupling using the commercially
available boronic acid. Another approach was developed where
acetylene or vinyl boronate precursors would have been difficult
to obtain. The corresponding alkenes were hydroborated to yield
alkylboranes quantitatively, which were directly utilized in a one-
pot, sp2-sp3 Suzuki coupling with 3 to obtain 4f-h. In the case of
4f the alkene precursor was synthesized in one step (see
supporting information). Conditions were optimized in each case
to obtain good selectivity and suppress dehalogenation.
Following side chain installation, the double (or triple) bond
was saturated, the nitro group was reduced, and the aryl-Cl bond
was hydrogenolized in the same hydrogenation step.
Optimization and screening were required to find ideal conditions.
Eventually, HCOONH4 proved to be an excellent transfer
hydrogenation agent and, in most cases, side reactions were
suppressed. Finally, methyl ester and trifluoroacetamide
hydrolysis followed by Fmoc installation afforded 1a-h on a 0.57-
1.30 g scale. The final products were purified by normal phase
flash chromatography and preparative RP-HPLC to reach the
desired purity (>99%) for solid phase foldamer synthesis.
Sequence 5 (Fig. 2a) was designed to validate side chain
positions using the new Q6Xxx monomers and to possess some
side chain diversity (eight different aromatic monomers). Manual
solid phase synthesis[20] provided outstanding crude purity (Fig.
1
2b). The spreading of H NMR signals in DMSO-D6 of aromatic
amide protons (Fig. 2c) is characteristic of helix folding. Derivative
6 was prepared to have a slightly better water solubility and was
set to crystallize from water/acetonitrile using the hanging drop
method. Crystals that diffracted up to a resolution of 1.2 Å were
obtained and the structure was solved in the P-1 space group with
two independent molecules in the asymmetric unit (Fig. 2d-2f).
Figure 2d shows an array of hydrophobic QXxx and 6-substituted
Q6Xxx monomer side chains arranged as predicted in Figure 1b.
An overlay with the predicted model demonstrates an RMSD of
0.4 Å of the first atom of each side chain, establishing the good
prediction of side chain position by a simple molecular modelling
tool, and the weak deviation of the structure of 6 from an ideal
calculated helix (Fig. S5). Furthermore, pairs of parallel helices
are observed in which two arrays of hydrophobic groups cluster
and interdigitate (Fig. 2e), as in -helix peptide bundles.[21] The
two helices nevertheless have opposite handedness and opposite
Figure 2. a) Sequences 5 and 6. b) Crude C18 RP-HPLC profile of 5. c) Part of
the crude 1H NMR spectrum of 5 in DMSO-D6 showing the expected twelve
aromatic amide resonances. Data for purified samples are shown in the
Supporting Information. d)-f) Crystal structure of 6. d) Views showing the side
chains of QLeu2, Q6Phe5, QLeu7, Q6Phe10 and QLeu12 in CPK view with the same
color code as in Figure 1b. The rest of the structure is shown in grey tubes. e)
Views of a discrete dimer with interdigitated hydrophobic side chains (same
residues as in d). f) Side chain-main chain hydrogen bonding involving the
ammonium of QDap1 and an amide carbonyl oxygen atom (dN-O = 2.83 Å), and
side chain-side chain proximity between QOrn6 and QTyr4. Note the ammonium
group of QOrn6 was placed at a hypothetical position as, unlike the three carbons
of the side chain, it cannot be located in the electron density map. Some
hydrogen atoms are shown at calculated positions but were not included during
refinement. Solvent molecules have been removed for clarity.
3
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N→C polarity, an assembly mode that has already been observed
in helix bundles.[22] In solution, water rich samples only show
broad 1H NMR lines (Fig. S5), suggesting that no well-defined
aggregate prevails. Nevertheless, the structure of 6 clearly hints
at the possibility to design knob-into-hole complementary
hydrophobic interfaces similar to those of -helices.
Notwithstanding a certain disorder of the side chains resulting in
partial occupancy factors, additional remarkable features of this
structure include likely side chain-main chain hydrogen bonding
(Fig. 2f left) and also some proximity between Orn and 6Tyr side
chains hinting at possible intramolecular cation- interactions (Fig.
2f right). Side chain-side chain interactions are indeed well-known
to influence -helix stability.[23] Qn helices are intrinsically very
stable and need no further stabilization. Nevertheless, such
interactions would help to fine tune the stability of related
sequences having stronger dynamics.[24]
Altogether, these results establish the suitability of
substituted Qn oligomers as scaffolds to mimic some extended
arrays of side chains at the surface of long -helices. Interestingly,
sequences that combine Q monomers and -amino acids do not
provide such a good match.[25] Prospective applications of these
mimics include the recognition of protein surfaces and the
construction of peptide bundles. Progress in these directions is
being made in our laboratories and will be reported in due course.
Feyfant, WO/2013/123266, 2013.
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Acknowledgements
Part of this research has been implemented in the frame of the
project FIEK_16-1-2016- 0005 “Development of molecular
biomarker research and service center”, with the support provided
from the National Research, Development and Innovation Fund
of Hungary, financed under the FIEK_16 funding scheme. This
work was also supported by the European Union (H2020-MSCA-
IF-2016-751019-PROFOLIG, postdoctoral fellowship to P.S.R.).
It benefited from the facilities and expertise of the Biophysical and
Structural Chemistry platform at IECB, CNRS UMS3033,
INSERM US001, Université de Bordeaux. We thank Marine
Stupfel for preliminary contributions and Daniel Bindl for assitance
with NMR measurements. Synchrotron data were collected at
beamline P13 operated by EMBL Hamburg at the PETRA III
storage ring (DESY, Hamburg, Germany). We thank Saravanan
Panneerselvam for assistance in using the beamline.
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Keywords: aromatic foldamers • -helix • peptidomimetics •
structure based design • structure elucidation
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Different yet alike. Aromatic helices may be designed to display side chain patterns mimicking the surface of an extended -helix
despite the considerable differences between the geometrical parameters of their backbones.
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