Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

Article abstract of DOI:10.1002/chem.202000924

Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]⁶-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT₂R/AT₁R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21.

Full text of DOI:10.1002/chem.202000924

Accepted Article
Accepted Article
Title: Single peptide backbone surrogate mutations to regulate
angiotensin GPCR subtype selectivity
Authors: Eirinaios I. Vrettos, Ibai E. Valverde, Alba Mascarin, Patrick
N. Pallier, Linda Cerofolini, Marco Fragai, Giacomo Parigi,
Baydaa Hirmiz, Nick Bekas, Nathalie M. Grob, Evgenios
Stylos, Hamidreza Shaye, Mark Del Borgo, Marie-Isabel
Aguilar, Francesca Magnani, Nelofer Syed, Timothy Crook,
Emal Waqif, Essam Ghazaly, Vadim Cherezov, Robert E
Widdop, Claudio Luchinat, Adina T. Michael-Titus, Thomas L.
Mindt, and Andreas Tzakos
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202000924
Link to VoR: https://doi.org/10.1002/chem.202000924
01/2020

10.1002/chem.202000924
Chemistry - A European Journal
COMMUNICATION
Single peptide backbone surrogate mutations to regulate
angiotensin GPCR subtype selectivity
Eirinaios I. Vrettos a, Ibai E. Valverde d,e, Alba Mascarin d, Patrick N. Pallier h, Linda Cerofolini o, Marco
Fragai j,o, Giacomo Parigi j,o, Baydaa Hirmiz b, Nick Bekas a, Nathalie M. Grob m, Evgenios Stylos a
,
Hamidreza Shaye p, Mark Del Borgo b, Marie-Isabel Aguilar b, Francesca Magnani n, Nelofer Syed k,
Timothy Crook l, Emal Waqif h, Essam Ghazaly i, Vadim Cherezov p, Robert E Widdop c, Claudio
Luchinat j,o, Adina T. Michael-Titus h, Thomas L. Mindt *d,f,g, Andreas G. Tzakos *a
[a]
E. Vrettos, N. Bekas, E. Stylos, Ass. Prof. A. Tzakos
Department of Chemistry
University of Ioannina
Ioannina 45110, Greece
E-mail: atzakos@uoi.gr
[b]
[c]
[d]
[e]
[f]
B. Hirmiz, Prof. MI. Aguilar, Prof. M. Del Borgo
Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology,
Monash University
Clayton VIC 3800, Australia
Prof. R. Widdop
Monash Biomedicine Discovery Institute and Department of Pharmacology
Monash University
Clayton VIC 3800, Australia
Dr. I. Valverde, Dr. A. Mascarin, Prof. T. Mindt
Division of Radiopharmaceutical Chemistry
University of Basel Hospital
Petersgraben 4, CH-4031 Basel, Switzerland
Dr. I. Valverde
Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB)
Université de Bourgogne Franche-Comté
UMR 6302 CNRS-UBFC, Dijon, France
Prof. T. Mindt
Department of Biomedical Imaging and Image Guided Therapy
Medical University of Vienna
Vienna, Austria
[g]
[h]
[i]
Prof. T. Mindt
Ludwig Boltzmann Institute Applied Diagnostics
General Hospital of Vienna
Vienna, Austria
Dr. P. Pallier, E. Waqif, Prof. A. Michael-Titus
Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry
Queen Mary University of London
4 Newark Street, Whitechapel, London, E1 2AT, UK
Dr. E. Ghazaly
Centre for Haemato-Oncology, Barts Cancer Institute
Queen Mary University of London
London, UK
[j]
Prof. M. Fragai, Prof. G. Parigi, Prof. C. Luchinat
Centre for Magnetic Resonance, CERM
University of Florence
Sesto Fiorentino 50019, Italy
[k]
Dr. Nelofer Syed
John Fulcher Neuro-oncology Laboratory, Division of Brain Sciences, Faculty of Medicine
Imperial College London
London W6 8RP, UK
[l]
Prof. T. Crook
Leaders in Oncology Care
95 Harley Street, London, W1G 6AF, UK
N. Grob
[m]
Department of Chemistry and Applied Biosciences
ETH Zurich
CH-8093 Zürich, Switzerland
[n]
Prof. F. Magnani
Department of Biology and Biotechnology "Lazzaro Spallanzani"
1
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10.1002/chem.202000924
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University of Pavia
Pavia, Italy
[o]
Dr. L. Cerofolini, Prof. M. Fragai, Prof. G. Parigi, Prof. C. Luchinat
Consorzio Interuniversitario Risonanze Mgnetiche MetalloProteine (CIRMMP)
University of Florence
Sesto Fiorentino 50019, Italy
[p]
Prof. Vadim Cherezov, Hamidreza Shaye
Bridge Institute, Department of Chemistry,
University of Southern California,
Los Angeles, CA 90089, USA
Supporting information for this article is given via a link at the end of the document.
Abstract: Mutating the side-chains of amino acids in a peptide ligand,
with unnatural amino acids, aiming to mitigate its short half-life is an
established approach. However, we hypothesized that mutating
specific backbone peptide bonds with bioisosters can be exploited not
only to enhance the proteolytic stability of parent peptides, but also to
tune its receptor subtype selectivity. Towards this end, we
synthesized four [Y]6-Angiotensin II analogs where amide bonds have
been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four
different backbone locations. All the analogs possessed enhanced
stability in human plasma in comparison with the parent peptide,
whereas only two of them achieved enhanced AT2R/AT1R subtype
selectivity. This diversification has been studied through 2D NMR
vivo, mostly due to their fast proteolytic degradation. In this frame,
various methods have been invoked to mitigate their instability
through the installation of amide-bond backbone surrogates such
as triazole[8],[9], four-membered oxetane ring[10], thioamide or ester
bonds[11] and methylated amide bonds[12]. However, despite being
considered crucial for peptide stabilization, peptide backbone
modification is not considered yet as a tool to tailor fundamental
pharmacological properties of bioactive peptides such as receptor
subtype selectivity.
Previously, we discovered a very potent and selective
peptide analog of angiotensin II (AII), [Y]6-Angiotensin II
designated as [Y]6AII (His6 is substituted by Tyr6), that presented
a 18.000 fold AT2R/AT1R GPCR subtype selectivity and low
nanomolar affinity for the AT2R[6]. This is of high importance since
the AT2R is responsible for tumor progression in some cancers,
tissue repair and neuron regeneration and is thus an important
pharmaceutical drug target. However, sensitivity to proteases and
consequently its low metabolic stability is a limitation for its further
clinical development. To overcome this problem, we conceived
the design of 4 novel analogs that bear 1,2,3-triazoles in strategic
locations within the sequence of [Y]6AII, as shown in Figure 1Α.
Along the sequence of each analog of [Y]6AII, one conventional
amide bond was mutated with a 1,4 disubstituted 1,2,3-triazole
(the synthetic procedure is depicted in Scheme S1 and the
characterization details are presented in Figures S1 to Figure
S24 as also in Table S1). We selected the specific backbone
positions because a modification of Phe or Pro might impede the
AT2R selectivity[13] and the stabilization of the Asp-Arg bond with
a triazole was not prioritized, as the cleavage of this bond leads
to the active peptide Ang(2-8)[14]. The triazole heterocycle mimics
the geometric, steric and electronic features of an amide bond and
likewise participates in hydrogen bonding and dipole-dipole
spectroscopy and unveiled
a
putative more structured
microenvironment for the two selective ligands accompanied with
increased number of NOE cross-peaks. The most potent analog,
compound 2, has been explored regarding its neurotrophic potential
and resulted in an enhanced neurite growth with respect to the
established agent C21.
G-protein-coupled receptors (GPCRs) are the targets of
approximately 35% of approved drugs[1] and are major signal
transducers in higher eukaryotes. GPCRs exist as subtypes and
although they share sequence and structure homology, they can
present opposing activities. This is the case of the renin-
angiotensin system (RAS), a pathway involved in intravascular
volume regulation, where two receptors exist: the AT1R
(Angiotensin Receptor subtype 1) and the AT2R (Angiotensin
Receptor subtype 2). The AT1R is responsible for cell proliferation,
angiogenesis, oxidative stress and cardiovascular dysfunctions,
while the AT2R has been reported to counteract several of the
effects mediated by the AT1R, conferring cardio-protection[2],
antiproliferation, antiinflammation and neuroregeneration[3].
Recently, we identified that AT2R can provide therapeutic
opportunities in melanomas[4], human pancreatic ductal
adenocarcinoma[5] and breast cancer[6]. In addition, we showed
that AGTR1 CpG island methylation in serum could serve as a
novel biomarker of metastatic melanoma[4]. These discoveries
were feasible due to the establishment of our selective compound,
[Y]6-Angiotensin II, for the AT2R[6]. With an increasing body of
evidence indicating that selective targeting of AT2R can provide a
better treatment for many different diseases[7], there is an
imminent need to further develop angiotensin receptor subtype-
selective ligands.
interactions[15]
.
As a consequence, a crucial factor that should be evaluated
first was the human plasma stability and whether the backbone
location of the bioisostere affects the half-life of the
peptidomimetics. For this we set up LC-MS protocols to monitor
their stability in human plasma (Figure 1Β). After 24 h of plasma
incubation, the four analogs were fully stable with a degradation
percentage of about 10%, while only 64% of the initial
concentration of [Y]6AII remained intact from plasma proteases
activity. It became evident that the replacement of amide bonds
by the 1,2,3-triazole bioisosteres in different backbone positions,
enhanced profoundly the stability of [Y]6AII in human plasma.
Afterward, the binding affinity and selectivity of the
synthesized analogs of [Y]6AII were evaluated, as they should
remain in similar or enhanced values with respect to the parent
peptide. [Y]6AII possesses enhanced binding affinity towards
Traditionally, synthetic peptides have served as invaluable
tools to probe selectivity of peptidergic GPCR, like AT1R and
AT2R. Conventionally, side-chains of a lead peptide sequence are
mutated. However, to further exploit peptides as drugs, the main
obstacle that has to be surpassed is their inherent low stability in
2
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AT2R with respect to the native hormone[6], and to this end, we
utilized human embryonic kidney cells (HEK-293), stably
transfected with either the AT1R or the AT2R, and determined the
relative selectivity of the new analogs. Competition for 125I-[Sar1,
Ile8]AII (Figure S25) binding in the HEK-293 cells transfected with
the AT1R was observed only for AII and none of the compounds
1-4 illustrated any competitions (Figure 2A). On the other hand,
in HEK-293 cells transfected with AT2R, competitive binding for
125I-[Sar1, Ile8]AII was observed with all compounds (1-4),however
compounds 2 and 4 pinpointed superior affinity in comparison to
compounds 1 and 3 (Figure 2B). To determine the relative AT2R
selectivities of the synthetic ligands, the ratio of IC50 values at
AT1R/AT2R was evaluated (Table S2). The rank order of affinity
at AT2R was compound 2 > compound 4 > compound 3 >
compound 1.
Figure 2. Competition-binding experiments for AII and the four peptidomimetic
analogs against 125I-[Sar1, Ile8]AII binding performed in HEK-293 cells stably
expressing: A. AT1R or B. AT2R. Results are the competition binding from three
separate experiments (each in triplicate).
Based on the monitored diversification of the AT2R/AT1R
selectivity into two groups of compounds, we set out to explore
the structural microenvironment of the 4 analogs in solution with
high-resolution 2D NMR spectroscopy. The full resonance
assignment was achieved for all analogs (Tables S3-S6). By
overlapping the NH/HA region of the 2D 1H-1H TOCSY NMR of all
analogs (Figure 3A), it is evident that the signals of compounds
2 and 4 are significantly more spread than those of compounds 1
and 3 (peaks of compound 2 in the ranges of 7.38-8.75 and 3.84-
5.19 ppm and of compound 4 in the ranges of 7.21-8.87 and 4.01-
5.07 ppm; peaks of compounds 1 in the ranges 7.54-8.61 and
3.99-4.81 ppm and of compound 3 in the ranges 7.25-8.57 and
3.98-4.72 ppm. Similarly, the NH-NH NOE signals, according to
1H-1H 2D NOESY experiments (Figure S26), of compounds 2 and
4 between their residues are more spread and reach to higher
ppm values, with respect to compounds 1 and 3, suggesting the
formation of more compact structures in solution. Interestingly,
the number of cross-peaks between the NH protons of amino
acids and the neighboring triazole ring proton (TriH) increases
going from compounds 1 and 3 (with 1 and 2 cross-peaks,
respectively) to compounds 4 and 2 (with 3 and 4 cross-peaks,
respectively), as shown in Figure 3B.
This trend is in accordance with the stratification of the
compounds according to the AT1R and AT2R affinity experiments,
and specifically on their relative AT2R selectivities. Compounds 2
and 4 that present enhanced relative selectivity for AT2R, present
similar NMR spectroscopic data, with respect to compounds 1 and
3 bearing lower AT2R selectivity. The enhanced number of cross-
peaks between NH and TriH, recorded for compounds 2 and 4,
could potentially indicate the formation of a more compact
structural microenvironment driven by the triazole ring, with
respect to compounds 1 and 3. The observed compound
stratification by NMR is proportionating to the recorded
Figure 1. A. Structures of the four analogs of [Y]6AII in which specific amide
bonds have been replaced with triazole isosteres; B. Human plasma stability of
[Y]6AII and its analogs bearing 1,2,3-triazole isostere in various backbone
locations (standard deviation is indicated with error bars and the experiment
was conducted in triplicate).
Two of the novel [Y]6AII analogs presented enhanced
AT2R/AT1R subtype selectivity with respect to AII. Specifically,
compound 2 and compound 4 were >3611- and 1336- fold
selective, respectively for for AT2R over AT1R. In contrast, the
other two compounds presented minimal AT2R selectivity (5- and
64- fold for compound 1 and compound 3, respectively), although
their affinities for AT2R were reduced compared with AII itself. The
IC50 values for AT2R were calculated 2 µM, 2.8 nM, 155 nM and
7.5 nM for compounds 1, 2, 3 and 4, respectively (Table S2).
However, it is worth noting that since these compounds failed to
displace AT1R binding appreciably, their relative AT2R
selectivities may be conservative estimates.
3
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AT2R/AT1R subtype selectivity values. This could imply that the
favorable stereo-electronic environment offered by the specific
localization of the triazole rings[16] in compounds 2 and 4 could
potentially be responsible for the recorded more favorable affinity
for AT2R.
Figure 4. Neurotrophic effect of the non-peptide compound C21 (A), compared
to compound 2 (B), in mouse cortical neuronal cells, at different concentrations.
The graphs show the area covered by neurites per field of view, as means ±
SEM. *P < 0.05, **P < 0.01, ***P < 0.001 for treatment vs control group.
Experiments were conducted in triplicates.
In summary, we synthesized four peptidomimetic analogs of
[Y]6AII in which we mutated 4 amide bonds with 1,4 disubstituted
1,2,3-triazoles. These mutations led to enhanced proteolytic
profile with respect to the parent compound [Y]6AII. Furthermore,
2 of the 4 backbone mutations (compounds 2 and 4) pinpointed
that they retained their AT2R/AT1R selectivity, whereas the
backbone mutations in compounds 1 and 3 resulted in reduced
receptor binding and AT2R subtype selectivity. This differential
binding and selectivity profile was also projected in the recorded
2D
NMR spectra.
Specifically,
a
more structured
microenvironment was recorded (chemical shifts are dispersed in
higher spectral width, with higher number of NOE cross-peaks)
for compounds 2 and 4, than for the other two compounds.
Evaluation of the neurotrophic effect of compound 2 indicated that
backbone modification between Tyr4 and Ile5 led to an enhanced
neurite growth with respect to the established agent C21. In
conclusion, triazole bioisoster could pave the way for its
exploitation beyond its traditional use to enhancing the stability of
proteolytically unstable therapeutics. Installing the triazole ring in
specific peptide backbone locations could regulate the backbone
structure microenvironment of the peptide and modulate its
affinity for GPCRs. Thus, the peptide backbone could be exploited
in a heterodox way and specifically as a way to tailor the
selectivity in GPCR subtypes and in the same time enhance the
proteolytic stability of the parent peptides.
Figure 3. A. Overlapping of the NH/HA region of the 2D 1H-1H TOCSY spectra
of the four analogs; B. Overlapping of the NH/NH region of the 2D 1H-1H NOESY
spectra of the four analogs; Cross peaks in compound 1 are colored in black, in
compound 2 are colored in green, in compound 3 are colored in grey and in
compound 4 are colored in blue. Label ‘A’ refers to the cis conformers and ‘B’
to the trans conformers. ‘TriH’ stands for the proton of the triazole ring.
Finally, based on the neuroprotective features associated
by AT2R, we set to investigate the neurotrophic action of our lead
molecule, compound 2, and compare it with the established non-
peptide agonist compound 21 (C21), which has been reported to
increase an AT2R-mediated neurite growth by Namsolleck et.
al.[17], (synthesis is briefly described in Figure S27). Mouse
embryonic cortical neurons exposed for 48 hours to the
proteolytically stable compound 2 showed increased neurite
growth, as shown in Figure 4. Our results indicate that compound
2 enhanced neurite growth in primary neuronal cultures by 50 ±
10% (increase in the area covered by neurites), an effect that was
slightly enhanced compared to the established AT2R selective
non-peptide agonist C21 (40 ± 6%). Therefore, our lead
compound 2 may be considered as a novel therapeutic approach
for the treatment of spinal cord injury. A relevant activity could be
expected for the compounds 1, 3 and 4, though due to their
reduced AT2R selectivity they have not been evaluated in this
assay.
Acknowledgements
This work was co-financed by the European Union (European
Social Fund ESF) and Greek national funds through the
operational Program “Education and Lifelong Learning” of the
National Strategic Reference Framework (NSRF) & Research
Funding Program: ARISTEIA II [grant number: 5199]. The
research work was supported by the Hellenic Foundation for
Research and Innovation (H.F.R.I.) under the “First Call for
H.F.R.I. Research Projects to support Faculty members and
Researchers and the procurement of high-cost research
equipment grant” (Project Number: 991, acronym PROTECT). A
«Developmental Gap Fund Αward from the Medical Research
Council Technology, is acknowledged. Also, EIV would like to
state his gratitude for the funding of Greece and the European
Union (European Social Fund- ESF) through the Operational
programme “Human Resources Development, Education and
4
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10.1002/chem.202000924
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Lifelong Learning 2014-2020” in the context of the project
“Strengthening Human Resources Research Potential via
Doctorate Research - 2nd Cycle” (MIS 5000432). Finally, this
work was supported by the Swiss National Science Foundation
(grants Nr. 205321-132280, 200020-146385, and 200021-
157076 to T. L. M.)
Keywords: Click chemistry • Competition-binding experiments •
GPCR • Neurotrophic effect • Peptidomimetics
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Entry for the Table of Contents
Through backbone amide bond substitutions with 1,4-disubstituted 1,2,3-triazole rings in strategic positions, we enhanced the
proteolytic stability in human plasma and simultaneously tuned the AT2R/AT1R GPCR subtype selectivity and retained the neurotrophic
effects of peptide ligands derived from [Y]6-Angiotensin II.
6
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