Learning from Peptides to Access Functional Precision Polymer Sequences

Article abstract of DOI:10.1002/anie.201902217

Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.

Full text of DOI:10.1002/anie.201902217

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Angewandte
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Accepted Article
Title: Learning from peptides to access functional precision polymer
sequences
Authors: Eva Maron, Jordan H. Swisher, Joris Haven, Tara Y. Meyer,
Tanja Junkers, and Hans G. Börner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902217
Angew. Chem. 10.1002/ange.201902217
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10.1002/anie.201902217
Angewandte Chemie International Edition
COMMUNICATION
Learning from peptides to access functional precision polymer
sequences
Eva Maron,[1] Jordan H. Swisher,[2] Joris J. Haven,[3] Tara Y. Meyer,[2] Tanja Junkers,[3,4]* Hans G.
Börner[1]*
Abstract: Functional precision polymers based on monodisperse ol-
igo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy
acid)s are synthesized. The discrete sequences originate from a di-
rect translation of side chain functionality sequences of a peptide with
well-studied properties. This peptide was previously selected to sol-
ubilize the photosensitizer meta-tetra(hydroxyphenyl)-chlorin. The
resulting peptido-mimetic formulation additives are preserving the
drug solubilization and release characteristics of the parent peptide.
Ultimately in some cases even superior properties are offered reach-
ing up to 40% higher payload and 27-times faster initial drug release.
nities to explore advanced functions that rely on sequence-spe-
cific interactions.[8] Despite the progress on both the synthetic
and application fronts, the development of paradigms to guide
the sequence design of precision polymers has received little at-
tention. Peptides represent a model platform with well-investi-
gated sequence-function relationships, enabling to program e.g.
nanostructures, hierarchically self-assembled materials, drug-
specific carriers, and material-specific adhesives.[9] Several ap-
proaches have emerged for the de novo design of functional
peptides: (i) empiric, (ii) combinatorial, (iii) rational, (iv) bio-in-
spired and (v) computational design strategies.[10] The first two
approaches seem most applicable for the design of precision pol-
ymers, as all the other approaches are challenging due to the
lack of established structure-property relationships in non-biolog-
ical macromolecules.
Although nature provides valuable templates for engineering
properties by using sequences in biomacromolecules, the trans-
fer of these general principles to non-biological polymers still re-
mains challenging. Molecular precision in information-rich mac-
romolecules like RNA/DNA, oligosaccharides and peptides/pro-
teins is considered to be the key to the origin of highly selective
functions in biosystems.[1] Recently, this concept has been ex-
tended to precision polymers[2] that include monodisperse mac-
romolecules with discrete sequences from artificial monomer al-
phabets. This class of polymers broadly expands the chemical
space of backbone constituents and sidechain functionalities
compared to biomacromolecules. Precision polymers can be
prepared using solid-phase supported (SPS) synthesis[3] and so-
lution-phase strategies. The latter include radical chain-growth of
spontaneous sequence forming monomers, cyclopolymeriza-
tions of templated monomer pairs, and ring-opening metathesis
of cyclic macromonomers.[4] Moreover, radical polymerization
under single monomer insertion (SUMI) conditions and segmer
assembly polymerization (SAP) have proven particularly valua-
ble for accessing macromolecules with distinct monomer order.[5]
Sequence-defined macromolecules have already found use in
information coding to demonstrate data storage and anti‐coun-
terfeiting applications.[6] Moreover, discrete patterns in polarity
and functionality proved to be advantageous for antimicrobial
properties and self-assembly control.[7] Certainly the structural
and sequential spaces of precision polymers offer new opportu-
Figure. 1. Schematic illustration of the sequence transfer strategy from a pep-
tide-PEG conjugate to PEG conjugated precision sequences.
Herein, we describe a route for designing functional precision
polymers by translation of peptide sequences to precision poly-
mer backbones via monomer-to-monomer mapping of the pep-
tide side-chain functionalities (Fig. 1). A peptide that was previ-
ously selected to host meta-tetra(hydroxyphenyl)-chlorin (m-
THPC) as a photosensitizer for photodynamic cancer therapy
was chosen as a template.[11] Monodisperse N-substituted ol-
igo(acrylamide)s and α-carbon substituted oligo(ester)s were
synthesized by SUMI and SAP protocols. The m-THPC loading
and release properties of poly(ethylene glycol) (PEG) conjugated
precision sequences were analyzed and compared to properties
of the parent peptide-PEG conjugates.
The peptide-PEG conjugate QFFLFFQ-PEG was previously
shown to be a suitable solubilizer for m-THPC, reaching payload
capacities of up to 1:3.3 (mol ratio drug:carrier).[11-12] Intriguingly,
the peptide-sequence indicated drug structure specific hosting of
m-THPC and thus offers an interesting starting point to explore
peptido-mimetic precision polymers.[13] The sequence analysis
by systematic alanine substitution (Ala-scan), indicated the high
importance of the FFLFF segment for drug loading as substitu-
tion in this domain dramatically reduced loading.
[1]
E. Maron, Prof. H. G. Börner
Department of Chemistry, Humboldt-Universität zu Berlin
Brook-Taylor-Str. 2, 12489 Berlin, Germany
E-mail: h.boerner@hu-berlin.de
[2]
[3]
J. H. Swisher, Prof. T. Y. Meyer
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, US
Dr. J. J. Haven, Prof. T. Junkers
Polymer Reaction Design Group, School of Chemistry, Monash Uni-
versity, Rainforest Walk VIC 3800 Australia
Prof. T. Junkers
[4]
Institute for Materials Research, Hasselt University, Martelarenlaan
42, 3500 Hasselt, Belgium Krijgslaan 281 S4, 9000 Ghent, Belgium
Supporting information for this article is given by a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201902217
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COMMUNICATION
Figure 2. Synthesis of sequence defined oligomer-PEG conjugates by SUMI, yielding oligo(acrylamide)-PEGs (top) and by SAP, leading to poly(ester)-PEGs
(bottom). (Conditions: a) AIBN/CTA in dioxane/water; b) hexylamine/tributylphosphine, CHCl3; i) DCC/DPTS, DCM; ii) Pd/C, H2; iii) TBAF/AcOH, THF; iv) TFA/DCM)
Exchange of the polar Gln1 or Gln7 residues increased the
loading by 14% to 39%.[13] The single residue mutationrevealed
the importance of Leu4 for drug hosting. The gradual reduction in
hydrophobicity by substituting Leu4 in the peptide-PEG conjugate
with Val4 and Ala4 reduced payload by 58% and 92% (S.I. Tab.
S5). This finding is consistent with heme-face contacts inproteins
that often involve Leu residues for cofactor anchoring.[14]
sequences found in the parent peptide. As precision polymer plat-
forms, oligo(N-substituted acrylamide)s and oligo(2-substituted-
α-hydroxy acid)s were explored.
Monodisperse oligo(acrylamide)s show close chemical simi-
larity to peptides by preserving the amide functionality only shift-
ing it from the backbone into the side chain, thus establishing a
compact C-C-backbone. Unsubstituted acrylamide and acryla-
mides with benzyl, isobutyl, isopropyl or methyl N-substituents de-
fine the analogues monomer alphabet to Gln, Phe, Leu, Val and
Ala residues, required to mimic the QFFL(V/A)FFQ peptides. The
monodisperse oligomers were prepared by reversible addition–
fragmentation chain–transfer polymerization (RAFT) conducted
under SUMI conditions (S.I. and Fig. 2). Chain transfer agent
(CTA) 2-cyano-2-propyl ethyl trithiocarbonate mediated the
polymerization of the different acrylamides. The products were
purified after each extension step. After completion of the pen-
tamer sequences, the RAFT end-groups were aminolysed and
the ω-thiol functional penta(acrylamide)s reacted in an in-situ Mi-
chael addition with acrylamide-ω-functionalized PEG to yield the
SUMI-PEG conjugates (SUMIFFLFF-PEG, SUMIFFVFF-PEG and SU-
MIFFAFF-PEG).
The effects of the peptide sequence variation on drug release
kinetics were studied by a fluorescence-based assay. In m-
THPC/peptide-PEG complexes the drug is present in a non-active
transport state, because singlet O2 production and fluorescence
is not measurable, due to self-quenching. When BSA (bovine se-
rum albumin) is added, the drug transfers to form m-THPC/BSA
complexes and regains its activity that can be followed by fluores-
cence spectroscopy (S.I.).[11] While drug release retardation is of
interest for many drug transporters, m-THPC solubilization profits
from a fast release to blood plasma proteins to rapidly activate the
photosensitizer and prevent adverse effects like extended light
sensitivity of patients.[15] The initial release rates from drug-loaded
solubilizers were determined by first order derivatives of the re-
lease traces (S.I. Tab. S5) and suggest the importance of the
flanking Gln residues for release. While the lack of Gln1 and Gln7
leads to slow release, single GlnAla exchanges result in conju-
gates that still release with suitable rates. The impact of central
residue exchanges (Leu4Val4Ala4) on release kinetics is less
significant, compared to the effects on loading. For instance,
QFFAFFQ-PEG shows only a slightly faster release compared to
the parent conjugate (S.I. Fig. S29).
To decouple the backbone effects from the side chain se-
quence, a set of oligo(2-substituted-α-hydroxy acid) segments
with analogous side chain sequences was prepared by SAP pro-
tocols (S.I. and Fig. 2).[8]
isocaproic acid, -hydroxy-isovaleric acid,
phenylmethyl)- -2-hydroxy-4-carbamoylbutanoic acid constituted
L-
phenyllactic acid,
L-hydroxy-
L
L-lactic acid and N-(tri-
L
the monomer alphabet, corresponding to Phe, Leu, Val, Ala, and
Gln. Iterative Steglich esterification, deprotection and purification
steps produced the α-silyl-ω-benzyl-protected hexamers (Fig.2).
The final heptamer sequences were accessed by addition of a
silyl protected monomer at the deprotected hydroxyl functional α-
Taking into account the requirements for peptides to reach
high payload and effective release kinetics, precision polymers
were designed by direct translation of the side chain functionality
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10.1002/anie.201902217
Angewandte Chemie International Edition
COMMUNICATION
chain end. Deprotection of the carboxylate ω-chain end allowed
coupling of a monomethoxy PEG. Final deprotection yielded a set
of SAP-PEGs that includes SAPQFFLFFQ-PEG, the single point-mu-
tated sequences SAPQFFVFFQ-PEG and SAPQFFAFFQ-PEG as well
as the sequence isomers SAPQLFFFFQ-PEG and SAPQFFFLFQ-PEG
(S.I.).
hydrophobic segment, suggests specific binding interactions be-
tween drug and SUMI domains.
The solubilizer SAPQFFLFFQ-PEG exhibiting the directly trans-
lated peptide sequence, reached a m-THPC loading of 1:3.8 (mol
ratio drug:carrier). Normalized by mass of the functional segment,
this capacity matches well that of the parent peptide conjugate
(Fig. 3). Interestingly, SAPQFFVFFQ-PEG and SAPQFFAFFQ-PEG
bearing isopropyl and methyl substituents exhibited capacities of
1:6.3 (-41%) and 1:4.1 (-11%). This behavior varies from what
was observed in the peptide or SUMI solubilizers. Probably it
might be rationalized by the fact that the amide to ester translation
reduces the hydrophobicity contrast between backbone and side-
chains, such as the variation of iBu to iPr to Me provides little im-
pact. Sequence, however, appears to play a significant role for
these SAP segments. If the central Leu-analogue residue is
shifted, substantial loading capacity reductions of 22% and 59%
were observed for SAPQLFFFFQ-PEG and SAPQFFFLFQ-PEG. The
shift of the central residue destroys the FF-analogous dyads,
which will probably disturb - interactions to the chlorin structure.
Despite the structural relation of peptides and oligo(acryla-
mide)s, all m-THPC/SUMI-PEG complexes show slow release ki-
netics (Fig. 3, S.I. Tab. S5). Counterintuitively, the impact of side
chain alteration is evidently less dominant on release kinetics than
on payload capacities in case of SUMI-PEG solubilizers. Appar-
ently, the side chain amides of the oligo(acrylamide) provide in-
sufficient polarity to counterbalance the removal of both flanking
Gln-analogue residues. In this respect, the release properties of
the SUMI-PEG conjugates mimic the behavior of the parent pep-
tide-PEG solubilizer, which converts to a slow releaser in case of
removal of Gln1 and Gln7 (S.I. Fig. S29). Analyzing the peptides
showed that a single GlnAla exchange is tolerated (regardless
of Gln1 or Gln7) and preserve the fast release of the peptide-PEG
solubilizers. Therefore, faster release was expected by extending
the SUMIFFLFF segment with a small block of acrylamide residues,
leading to SUMIFFLFFQ3-PEG (Fig. 3). As predicted, the polar se-
quence variant showed dramatically enhanced release kinetics
from m-THPC/SUMIFFLFFQ3-PEG complexes, which are superior to
the performance of the parent QFFLFFQ-PEG solubilizer (Fig. 3).
The increased polarity of the SUMI-PEG solubilizer provides suf-
ficient interface activity to assist the m-THPC transfer from the
hydrophobic core of the drug/solubilizer complexes to BSA in the
aqueous phase. The delicate balance in the hydrophilicity/hydro-
phobicity along the SUMI segments evidently affects the de-
crease in payload capacity. These results highlight the im-
portance of the precision segment as the effect cannot simply be
a consequence of the extension of the polar PEG-block.
In order to investigate analogies to the peptide-PEG conju-
gates, the oligo(acrylamide)-PEGs and oligo(ester)-PEGs were
studied for both m-THPC loading capacities and release proper-
ties to BSA. Independently of the sequences, the SUMI-PEGs ex-
hibited slightly lower water solubility than the SAP-PEGs. This dif-
ference might be rationalized by stronger interchain interactions
of the amide functionalities offering H-bonding in close proximity
to the hydrophobic C-C-backbone. The solubilizers were loaded
with m-THPC by following a previously established forced-loading
protocol.[11] The loading led to a sample set of well-defined m-
THPC/solubilizer complexes in water. Dynamic light scattering
(DLS, S.I. Tab. S4) indicated for drug-loaded SUMI-PEGs, inde-
pendent of the sequence, aggregates with hydrodynamic radii
(RH) of 70-78 nm. The loaded SAP-PEGs, formed slightly bigger
aggregates with RH of 73-85 nm. Hence, all drug/solubilizer com-
plexes meet with RH < 100 nm and polydispersities below 0.05,
the requirements for biomedical applications.[16]
Figure 3. Drug-uptake (left) and release (right) properties of SUMI-PEG (top)
and SAP-PEG solubilizers (bottom) (Payload capacities were normalized to the
functional segment masses and values at columns correspond to molar ratio
drug:carrier).
The SUMIFFLFF-PEG solubilizer with the sequence from the
parent peptide reached the highest payload capacity of 1:2.3 (mol
ratio drug:carrier). This capacity corresponds to an increase of
40%, compared to the optimized peptide-PEG conjugate (Fig. 3).
Interestingly, the capacities of the SUMI-PEG constructs follow
the same trend as found in the peptide-PEG conjugates with sys-
tematic central residue substitutions. The Leu-analogue reached
the highest capacity, while a significant decrease from 1:4.3 to
1:7.6 (mol ratio drug:carrier) was observed in changing the central
isobutyl side chain to isopropyl (SUMIFFVFF-PEG) to methyl (SU-
MIFFAFF-PEG) (Fig. 3). The reduction in payload capacity from SU-
MIFFLFF-PEG to SUMIFFAFF-PEG is quite dramatic with 60%. The
observed sensitivity of the SUMI-PEG solubilizer payload, which
exceeds that expected for a decrease in volume fraction of the
Interestingly, all oligo(ester)s show a preferred burst-type of
release, which is associated with the molecular structures of the
SAP segments, as no hydrolytic degradation was evident during
loading and release experiments. The activativation of m-THPC
from SAP-PEG drug complexes proceed significantly faster than
observed in drug-complexes of the parent peptide-PEG conjugate
or the SUMIFFLFFQ3-PEG solubilizer (Fig. 3). For instance, m-
THPC/SAPQFFLFFQ-PEG complexes activate 70% of the releasa-
ble photosensitizer within 1.5 h, which seems to be suitable for
therapeutic applications. In this set of m-THPC/SAP-PEG com-
plexes the release rates were rather close, making a solid inter-
pretation difficult. However, both SAP-PEG solubilizers with iso-
sequences show even faster initial drug release rates compared
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10.1002/anie.201902217
Angewandte Chemie International Edition
COMMUNICATION
to the non-scrambled SAPQFFLFFQ-PEG (Fig. 3 & S.I. Tab. S5). The
presence of sequence specific interactions is suggested by the
fact that moving the Leu-analogue residue by one sequence po-
sition to give SAPQFFFLFQ-PEG that leads to the fastest initial re-
lease rates of the entire set. Probably, the single position change
weakens the interactions of the precision segment SAPQFFFLFQ
with m-THPC and increase the transfer rates to BSA. The set of
oligo(ester)s reveals that trans-solubilization is influenced primar-
ily by the functional sequences. The backbone structure, in turn,
appears to exhibit a significant effect on the release, as the back-
bone contributes to modulation of drug binding interactions,
phase-transfer capabilities and structural dynamics of the solubil-
izer segments in drug/solubilizer complexes.
In conclusion, the drug hosting peptide (QFFLFFQ) that was
identified to accommodate m-THPC could be directly translated
into sequences of precision polymers, which preserve properties
of the parent peptide. Two sets of peptido mimetic precision pol-
ymers, based on oligo(N-substituted acrylamide)s and oligo(2-
substituted α-hydroxyl acid)s were prepared. The corresponding
PEG conjugates mimic properties of the parent peptide-PEG drug
solubilizer, demonstrating up to 40% higher payloads and show-
ing the desired drug release profile. The SUMI-PEGs mimic the
sensitivity of the payload capacity on single point mutation of the
central Leu residue and show the same retardation of release ki-
netics on removal of the flanking Gln-analogues as found in anal-
ogous peptide sequences. The SAP-PEGs show less sensitivity
concerning central residue mutations, but had a clear sensitivity
of payload and release to monomer order. The translation strat-
egy might be broadly applicable for materials science applications
and guide the design of precision polymers where advanced func-
tions originate from sequence-specific interactions.
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Acknowledgements
H.G.B. acknowledges financial support by the European Re-
search Council under the European Union’s 7th Framework Pro-
gram (FP07–13)/ERC Consolidator grant “Specifically Interacting
Polymer-SIP” (ERC 305064). T.Y.M. acknowledges financial sup-
port from the National Science Foundation (CHE-1709144). Addi-
tional support for MALDI-TOF MS instrumentation was provided
by a grant from the National Science Foundation (CHE-1625002).
T.J. and J.J.H. are grateful for provision of the mass spectrometer
via the Hercules fund Belgium.
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Keywords: precision polymer • monodisperse polymers • se-
quence design • drug delivery system • peptide PEG conjugates
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10.1002/anie.201902217
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Eva Maron, Jordan H. Swisher, Joris J.
Haven, Tara Y. Meyer, Tanja Junkers,
Hans G. Börner*
Page No. – Page No.
Learning from peptides to access
functional precision polymer se-
quences
A new strategy to guide the sequence design for accessing functional precision pol-
ymers was described. For that purpose, a well-studied peptide that acts as a formu-
lation additive to solubilize a photosensitizer drug was used and the direct translation
of side chain functionality sequences towards precision polymer backbones, leads to
macromolecules, which mimic drug hosting and release properties of the parent pep-
tide.
This article is protected by copyright. All rights reserved.