10.1002/anie.202008992
Angewandte Chemie International Edition
RESEARCH ARTICLE
We report a unique ensemble of X-ray structures of
foldamer ligands mimicking p53 and SRC peptides bound to their
respective target proteins MDM2 and VDR. The foldamers under
scrutiny are N,N’-linked oligoureas, a class of foldamers which
adopt stable helical secondary structures and have been
proposed as possible α-helix mimics.[8, 25] Interfacing oligoureas
with peptides was used for the first time in this work to design
peptide-oligourea hybrids that disrupt PPIs. High affinity binders
were obtained within few rounds of optimization by carefully
designing oligourea sequences.
facilitate lead peptide optimization and the design of more efficient
and specific foldamer sequences as disruptors of PPIs or as
receptor ligands.
Acknowledgements
This work was funded in part by the ANR (ANR-15-CE07-0010),
by the Conseil Regional de Nouvelle-Aquitaine (2017-1R10115)
and by SIRIC Brio. A CIFRE support from UREKA Pharma SAS
and ANRT to L. M. is gratefully acknowledged. This work has
benefited from the facilities and expertise of IECB Biophysical and
Structural Chemistry platform (BPCS), CNRS UMS3033, Inserm
US001, Univ. Bordeaux. The authors acknowledge the support
and the use of resources of the French Infrastructure for
Integrated Structural Biology FRISBI ANR-10-INBS-05, the
Instruct-ERIC. The authors thank the staff of Proxima 2 at
synchrotron SOLEIL and of ID23 and ID30 at ESRF for assistance
in using the beamlines. G. G. is grateful to Céline Reverdy and
Jean-Christophe Rain (Hybrigenics Services) for helpful
discussions. N. R. thanks Claude Ling and Bruno Kieffer (IGBMC)
for NMR measurements of ligand concentrations.
The high resolution structures collected here confirm that a
high degree of α-helix mimicry was achieved in the two series of
ligands. The approach is complementary to α-helix mimicry using
α/β-peptides.[7d] Whereas β-amino acid replacements are periodic
and follow a regular pattern along the sequence, our approach
employs a full oligourea to replace a α-helical segment. In most
cases the oligourea helix was correctly folded and the initial
design hypotheses were validated. The structures show that key
hydrophobic contacts are maintained and that the urea backbone
is able to recreate polar contacts with the protein surface, closely
mimicking those formed with the cognate peptide. The difficulty to
select the most appropriate side chains in ureido units to mimic a
given α-helical peptide segment comes in part from the larger
diameter of the oligourea helix and from the different spacing of
the side chains along the oligourea backbone compared to a
canonical α-helix. Replacing a peptide by an oligourea segment
thus requires key side chains to be specifically adjusted and
Keywords: Peptidomimetics • Foldamers • Protein-protein
interactions • Helical structures • Structure-activity relationships
[1]
[2]
E. Valeur, M. Guéret Stéphanie, H. Adihou, R. Gopalakrishnan, M.
Lemurell, H. Waldmann, N. Grossmann Tom, T. Plowright Alleyn, Angew.
Chem. Int. Ed. 2017, 56, 10294-10323.
positioned along the oligourea backbone. Similar to β- and γ-
26]
amino acid residues,[7h,
the increased diversity in terms of
position of substituents in ureido units (e.g. either on one or the
other backbone methylene or both) provides modularity and
additional opportunities to improve α-helix mimicry. This strategy
was employed successfully when designing hybrid 6, a p53
peptide mimic consisting of six α-amino acids and four ureido
units. In this case, introducing a monomer with an alternative
a) K. Fosgerau, T. Hoffmann, Drug Discov. Today 2015, 20, 122-128; b)
S. Mimmi, D. Maisano, I. Quinto, E. Iaccino, Trends Pharmacol. Sci. 2019,
40, 87-91; c) T. Passioura, T. Katoh, Y. Goto, H. Suga, Annu. Rev.
Biochem. 2014, 83, 727-752.
[3]
M. Erak, K. Bellmann-Sickert, S. Els-Heindl, A. G. Beck-Sickinger, Bioorg.
Med. Chem. 2018, 26, 2759-2765.
α
substitution pattern at one position (Lu ) was critical for α-helix
[4]
[5]
[6]
C. Morrison, Nat. Rev. Drug Discov. 2018, 17, 531.
A. L. Jochim, P. S. Arora, ACS Chem. Biol. 2010, 5, 919-923.
aK. Estieu-Gionnet, G. Guichard, Exp. Opin. Drug Discov. 2011, 6, 937-
963; bK. J. Skowron, T. E. Speltz, T. W. Moore, Med. Res. Rev. 2019,
39, 749-770.
mimicry. Another critical element of design is the choice of the
side chain to be introduced at a given position. A design principle
frequently applied when designing α-helix mimics based on α/β-
peptide is to introduce a β-residue that retain the original side
chain.[7d] Conversely, this approach is not always valid for
oligoureas and shorter side chains are sometimes more
appropriate as they can compensate for the increased diameter
of the oligourea helix (e.g. Vu to mimic L in 4, Figure 2F).
By interacting with N- and C-terminal backbone amides of a
short α-helical segment, the charge clamp at the surface of VDR
precisely selects coregulatory sequences of a given length and
can be used as a ruler to compare peptide and foldamer helices.
In this respect, X-ray structure analysis of 18 actually reveals that
the helical pentaurea segment is a very close mimic of the seven-
residue long α-helical region of peptide SRC2-3 (Figures 4B and
S20).
[7]
a) W. S. Horne, T. N. Grossmann, Nat. Chem. 2020, 12, 331-337; b) M.
Pasco, C. Dolain, G. Guichard, in Comprehensive Supramolecular
Chemistry II (Ed.: J. L. Atwood), Elsevier, Oxford, 2017, pp. 89-125; c) V.
Azzarito, K. Long, N. S. Murphy, A. J. Wilson, Nat. Chem. 2013, 5, 161-
173; d) L. M. Johnson, S. H. Gellman, in Methods Enzymol., Vol. 523
(Ed.: E. K. Amy), Academic Press, 2013, pp. 407-429; e) H. Yin, G.-i.
Lee, K. A. Sedey, J. M. Rodriguez, H.-G. Wang, S. M. Sebti, A. D.
Hamilton, J. Am. Chem. Soc. 2005, 127, 5463-5468; f) W. S. Horne, L.
M. Johnson, T. J. Ketas, P. J. Klasse, M. Lu, J. P. Moore, S. H. Gellman,
Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 14751-14756; g) R. W. Cheloha,
A. Maeda, T. Dean, T. J. Gardella, S. H. Gellman, Nat. Biotech. 2014, 32,
653-655; h) S. Liu, R. W. Cheloha, T. Watanabe, T. J. Gardella, S. H.
Gellman, Proc. Nat. Acad. Sci. U.S.A. 2018, 115, 12383-12388; i) B. B.
Lao, K. Drew, D. A. Guarracino, T. F. Brewer, D. W. Heindel, R. Bonneau,
P. S. Arora, J. Am. Chem. Soc. 2014, 136, 7877-7888; j) C. M. Grison, J.
A. Miles, S. Robin, A. J. Wilson, D. J. Aitken, Angew. Chem. Int. Ed. 2016,
55, 11096-11100; k) P. Sang, M. Zhang, Y. Shi, C. Li, S. Abdulkadir, Q.
Li, H. Ji, J. Cai, Proc. Nat. Acad. Sci. U.S.A. 2019, 116, 10757-10762.
J. Fremaux, C. Venin, L. Mauran, R. H. Zimmer, G. Guichard, S. R.
Goudreau, Nat. Commun. 2019, 10, 924.
The strategy reported here, whereby an α-helical segment
is replaced by a foldamer insert, may thus yield peptide analogues
with substantial resistance to proteolytic degradation, a feature
which is often desirable when developing peptide therapeutics.[3,
8] We expect this approach to be versatile enough to be combined
with other known peptide stabilization methods (e.g. β-amino acid
[8]
[9]
N. Pendem, C. Douat, P. Claudon, M. Laguerre, S. Castano, B. Desbat,
D. Cavagnat, E. Ennifar, B. Kauffmann, G. Guichard, J. Am. Chem. Soc.
2013, 135, 4884-4892.
replacement,[7d] macrocyclization,[4] lipidation[27]
)
to further
increase helical content, potency, and resistance to proteases.
The general principles that have been discussed here may thus
7
This article is protected by copyright. All rights reserved.