Homoallylglycine residues are superior precursors to orthogonally modified thioether containing polypeptides

Article abstract of DOI:10.1039/c8cc03048k

Homoallylglycine N-carboxyanhydride, Hag NCA, monomers were synthesized and used to prepare polypeptides containing Hag segments with controllable lengths of up to 245 repeats. Poly(l-homoallylglycine), G^HA, was found to adopt an α-helical conf

Full text of DOI:10.1039/c8cc03048k

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Homoallylglycine residues are superior precursors to orthogonally
modified thioether containing polypeptides†
a
a
a,b
Pesach Perlin, Eric G. Gharakhanian, and Timothy J. Deming
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Homoallylglycine N-carboxyanhydride, Hag NCA, monomers were block copolypeptide synthesis, high efficiency in subsequent
synthesized and used to prepare polypeptides containing Hag thiol-ene modifications, and control of chain conformations.
segments with controllable lengths of up to 245 repeats. Poly(L-
HA
homoallylglycine),
G , was found to adopt an -helical
conformation, which provided good solubility in organic solvents
and allowed high yield functionalization of its alkene side-chains via
radical promoted addition of thiols. The conformations of these
derivatives were shown to be switchable between -helical and
disordered states in aqueous media using thioether alkylation or
oxidation reactions. Incorporation of GHA segments into block Scheme 1. (A-E) Alkene containing homopolypeptides used for thiol-ene
copolymers with poly(L-methionine), M, segments provided a conjugation.
means to orthogonally modify thioether side-chains different ways
The simplest alkene containing polypeptides used for thiol-
in separate copolypeptide domains. This approach allows ene functionalization are based on allylglycine (Scheme 1A).
preparation of functional polypeptides containing discrete domains Both poly(L-allylglycine) and poly(DL-allylglycine) have been
of oxidized and alkylated thioether containing residues, where prepared and were found to adopt
-sheet conformations,
chain conformation and functionality of each domain can be which result in aggregation and limit the ability to prepare high
4
independently modified.
molecular weight chains. Consequently, efficient thiol-ene
functionalization of these polymers was restricted to samples
with short chain lengths (i.e. typically < 20 residues), and often
required incorporation of comonomers or segments (i.e. PEG)
There has been considerable recent interest in the development
of methods to selectively introduce functional tags into peptide,
protein, and polypeptide sequences. Among these, the thiol-
1
5
to promote solubility. Related polypeptides have been
prepared based on alkene functionalized serine and cysteine
residues (Scheme 1B,C) that also adopt -sheet conformations
leading to poorly controlled chain aggregation, which would be
problematic for downstream use as segments in block
copolypeptide assemblies.
2
ene reaction has been used extensively, since it can provide
6
7
modifications with high yields and high functional group
selectivity. For polypeptides, many unnatural alkene containing
residues have been employed for subsequent thiol-ene

3
modification (Scheme 1). In these examples, the side-chain
structures of these alkene amino acid residues have substantial
influence on resulting polypeptide chain lengths,
conformations, solubility, and consequently the efficiency of
thiol-ene conjugations. We sought to optimize the design of
alkene containing residues to enable robust polypeptide and
Additional studies have utilized functionalized glutamate
esters as components for preparation of alkene containing
polypeptides (Scheme 1D,E). These polypeptides have the
8
advantage of adopting -helical conformations, which possess
good solubility and allow formation of high molecular weight
chains. Homopolypeptides up to 100 residues long were
prepared and could be efficiently modified with different thiols
a.Department of Chemistry and Biochemistry, University of California, Los Angeles,
CA 90095.
yielding -helical derivatives. While this strategy is useful for
b.
Department of Bioengineering, University of California, Los Angeles, CA 90095.
preparation of homopolypeptides, the labile side-chain ester
linkages would be problematic in preparation of multifunctional
Corresponding author: demingt@seas.ucla.edu.
Electronic Supplementary Information (ESI) available: [Supporting figures S1-8,
tables S1-2, schemes S1-2, experimental procedures and spectral data for all new
compounds]. See DOI: 10.1039/x0xx00000x
9
copolypeptides. Also, this strategy only allows for preparation
of polypeptides with
-helical conformations, which cannot be
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switched due to their long, hydrophobic side-chains.8
Polypeptides with conformations that can be switched acid precursors were prepared following literature methods
reversibly under mild conditions are desirable for use in (see Scheme S1, ESI†).12,13 rac-Hag was obtained by alkylation of
development of self-assembled materials such as nanocarriers diphenylimino glycine tert-butyl ester, which gave the free
and hydrogels that can actively respond to biological and amino acid directly upon hydrolysis of the protecting groups.
Journal Name
For NCA monomer preparation, the Hag and rac-Hag amino
View Article Online
DOI: 10.1039/C8CC03048K
chemical cues.
Hag was prepared by alkylation of diethyl acetamidomalonate,
followed by ester deprotection and decarboxylation to give N-
acetyl-rac-Hag. This racemic mixture was readily resolved by
enantioselective hydrolysis catalyzed by porcine acylase to give
multigram quantities of Hag (see Figures S1-2), which possessed
an enantiomeric excess of >99% suitable for preparation of
NCAs and polypeptides with high optical purity. Analysis of both
12,13
Hag and rac-Hag matched literature data.
Hag and rac-Hag
Scheme 2. Comparison of allyl, homoallyl, and pentenyl glycine
homopolypeptides.
were each subsequently treated with phosgene under standard
conditions to obtain the corresponding NCAs that were
obtained as high purity colorless solids after column
To take full advantage of the thioether functionality
introduced by thiol-ene conjugation, we sought to develop
polypeptides containing alkene side-chains of minimal length so
that modifications of product thioether groups would induce
switchable chain conformations.10 Further, to enable
preparation of soluble, high molecular weight chains,
conformations were desired for the initial alkene bearing
polypeptides. While poly(allylglycine)s are known to form
14
chromatography and recrystallization (see Figures S3-4).
Figure 1. Synthesis and properties of poly(L-homoallylglycine), GHA. (A)
30
4
A
B
25
-helical
2
0
20
15
10
5

-
sheets, it has also been reported that poly(L-pentenylglycine)
-2
4
adopts an
-helical conformation (Scheme 2). While poly(L-
-4
pentenylglycine) has not been used for thiol-ene conjugation,
its hydrophobic side-chains might be too long to allow
conformational switching, similar to the glutamate derivatives
described above. Since single carbon homologation of side-
2
0
30 40 50 60 70 80
M:I
190 200 210 220 230 240
Wavelength (nm)
Number average molecular weight (M
n
) of GHA plotted as a function of
monomer to initiator ratio (M:I) at complete monomer conversion using
2
1
Co(PMe
3
)
4
in THF (r = 0.9874). M values were determined by H NMR
n
chain functional groups in
result in polypeptides that adopt
as homologation of cysteine to homocysteine,
hypothesized that the intermediate side-chain length of Hag

-sheet forming polypeptides can
analysis of PEG end-capped polymers. (B) Circular dichroism spectrum
of GHA in 15:1:2 cyclohexane:MeCN:IPA (0.5 mg/mL) at 20 C. Molar
ellipticity reported in deg·cm /dmol.
Homopolymerizations of Hag and rac-Hag NCAs at different
monomer to initiator (M:I) ratios were conducted using
Co(PMe ) initiator in THF. While Hag NCA polymerizations
3 4
rapidly went to completion and remained homogeneous up to
M:I = 80 (Figure 1A), the rac-Hag NCA polymerizations did not
go to completion above M:I = 20 (see Tables S1-2, Figure S5). By

-helical conformations, such
o
11
we
2
would be sufficiently long to stabilize -helical conformations in
HA
G
and yet be short enough to allow introduced thioether
1
5
groups to influence chain conformations (Scheme 2). Notably,
Hag has also been utilized as an artificial residue for efficient
thiol-ene modification in proteins.12
Consequently, we sought to develop procedures for
preparation of new NCA monomers of L-Hag and rac-Hag, and
synthesize their corresponding new homopolypeptides
HA
FTIR we observed the poly(DL-homoallylglycine), (rac-G )
,
forms
inhibit chain growth (see Figure S6). On the contrary,
homopolymers were found to be highly -helical in organic
-sheet aggregates during polymerization that likely
4
HA
G
(Scheme 3). To enhance the ability to prepare multifunctional

polypeptides with stimulus responsive conformations, we also
sought to prepare block copolypeptides of Hag with L-
methionine, Met. Specifically, we aimed to utilize Hag residues
as “masked” precursors of thioether groups, which could be
functionalized orthogonally to the thioether groups in Met
residues. The goal of this approach being the preparation of
block copolypeptides where discrete domains can be
functionalized and conformationally switched independent of
solvents (Figure 1B), which promoted good solubility and
enabled the synthesis of polymers up to 245 residues long.
Analysis of chain lengths at different M:I showed linear chain
growth during Hag NCA polymerization, an indicator of
controlled polymerization (Figure 1A). GPC analysis of
samples, derivatized using thiol-ene reactions to improve
solubility (Figure 2), gave unimodal peaks with dispersities of ca.
.1-1.2, confirming the formation of uniform polymers. To
HA
G
1
further test the ability of Hag NCA to undergo controlled
polymerization, diblock copolypeptides with Met NCA were
prepared (Table 1). Block copolypeptides of defined sequence
and composition were obtained in excellent yields, and GPC
analysis of derivatized copolymers (vide infra) showed uniform
chain length distributions with low dispersity (Figure 2).
one another.
Scheme 3. Synthesis of homoallylglycine NCAs and polypeptides.
2
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Compositions
1st Monomera 2nd Monomera
0 Met NCA
0 Hag NCA
First Segmentb
Diblock Copolymerc
View Article Online
DOI: 10.1039/C8CC03048K
M
6600
12800
n
DP
50
27
M
1.27
1.14
w
/M
n
M
9200
27400
n
DP
74
M
1.32
1.18
w
/M
n
Yield (%)d
2
1
10 Hag NCA
30 Met NCA
99
99
107
o
a
Table 1. Synthesis of diblock copolypeptides using Co(PMe
3
)
4
in THF at 20 C. First and second monomers added stepwise to the initiator; number
b
1
indicates equivalents of monomer per Co(PMe
)
3 4
. Molecular weight and dispersity after polymerization of the first monomer determined by H NMR
c
1
and GPC of derivatized polypeptide. Molecular weight and dispersity after polymerization of the second monomer determined by H NMR and GPC of
d
derivatized copolypeptide. Total isolated yield of diblock copolypeptide. DP = number average degree of polymerization.
After successful polymerization of Hag NCA, the reactivity of Figure 4. Circular dichroism spectra of functionally modified GHA63
GHA with a variety of thiols was evaluated. Toward the goal of samples. (A) Thiol-ene adducts mEG
-GHA (blue), mEG
-GHA (red), EG
-GHA in
-helix) and its sulfonium (black,
-
3
4
4
obtaining water soluble derivatives, oligoethylene glycol and GHA (black), Glc-GHA (green). All samples in DI water except mEG
monosaccharide thiols were chosen for these studies (Figure 3). THF. (B) parent mEG
-GHA (blue, 71%
Under optimized conditions, near quantitative thiol-ene 0% -helix) and sulfoxide (red, 22%
3
4


-helix) derivatives in DI water. All
o
functionalization of Hag residues was obtained for all thiols (see samples (0.5 mg/mL) analyzed at 20 C. Molar ellipticity reported in
12
HA
2
SI). For comparison, thiol-ene functionalization of (rac-G ) deg·cm /dmol. Percent
-helix content for each sample was calculated
was also attempted using similar conditions (see SI). While >
8
0
9
0% thiol conjugation efficiency could be obtained on short
HA
HAM
HAO
HA
1
20
90
60
30
0
A
= EG -G
B
= mEG -G
4
4
HA
60
(rac-G ) chains, these derivatives exhibited poor water
HA
HA
=
=
=
mEG -G
= mEG -G
4
4
40
solubility due to the formation of
S7). Contrary to this result, all thiol-ene derivatives of
found to possess good water solubility, except for mEG -G ,
3

-sheet structures (see Figure
mEG -G
= mEG -G
3
20
0
4
HA
G
were
HA
HA
Glc-G
-
20
40
which was soluble in organic solvents.
-30
60
-
-
1
90 200 210 220 230 240
190 200 210 220 230 240
Wavelength
2.5
2.0
1.5
1.0
0.5
0.0
Wavelength
=
HA
from its molar ellipticity at 222 nm using the formula %
θ]222 + 3000)/39000).16
Since functionalized GHA contain thioether linkages, there is
potential for additional secondary modification of the
polypeptide side-chains via selective alkylation or oxidation
reactions. To examine the feasibility of such modifications and
4
test their effects on polymer properties, mEG -G was reacted
separately with either iodomethane or tertbutylhydroperoxide
TBHP) to obtain the methylated derivative, mEG -G , or
4
-helix = 100·(-
Glc(OAc) -G
4
27
[
=
HA
M
Glc(OAc) -G 27M
4
80
S
1
0
HA
0
5
10 15 20 25 30
Time (Min)
HAM
(
HAO
4
oxidized derivative, mEG -G , respectively (Scheme 4). These
reactions gave high yields of the fully modified polypeptides,
HA
4
which retained the water solubility of the precursor mEG -G .
Figure 2. GPC Chromatograms of derivatized homo and diblock
-GHA27 (blue) and Glc(OAc) -GHA27MM80 (red) in
polypeptides Glc(OAc)
HAM
HAO
CD analysis of mEG
4
-G
and mEG
4
-G in water revealed that
-helical conformation of
the parent mEG -G (Figure 4B), similar to results obtained for
4
4
4
both modifications destabilized the

HFIP containing 0.5 % (w/w) KTFA. S = solvent. RIU = arbitrary refractive
index units.
HA
Figure 3. Thiol-ene modification of GHA
alkylation and oxidation of thioether containing
though the thioether groups in mEG -G
4
M
chains even
are two bonds
(4 mg/mL) in THF with UV
HAM
irradiation followed by overnight stirring at ambient temperature.
Funct = percentage of side-chain modification. Yield = total isolated
further removed from the peptide backbone compared to Met
residues. The degree of conformational disruption was
10
yield of purified polypeptide. quant. = quantitative
HAM
Aqueous solutions of GHA derivatives analyzed by circular
greater for mEG
4
-G , likely due to the introduction of charged
HAO
groups as compared to the non-ionic sulfoxides in mEG
4
-G
.
dichroism (CD) spectroscopy were found to primarily adopt


-
-
HA
This ability to switch between -helical and disordered
conformations in mEG -G polypeptides is a desirable feature
4
that has not been demonstrated in thiol-ene derivatives of
helical conformations, similar to the parent
G
(Figure 4A).
HA
Helical content was found to be greatest (ca. 100 % -helix) for
HA
4
the EG -G sample, which contained side-chains with greatest
other alkene containing polypeptides.
hydrophilicity. The methoxy terminated oligoethylene glycol
HA
HA
HA
HA
To illustrate how
G
segments can be used in conjunction
and glycosylated samples (mEG
3 4
-G , mEG -G , and Glc-G )
with other polypeptide segments to obtain chains with discrete
modified thioether domains, we sought to prepare diblock
copolypeptides containing both sulfoxide and sulfonium
functionality in separate segments (Scheme 5). Independent
possessed diminished minima at 208 and 222 nm, yet retained
partial helical content (49 to 71%
-helix). The addition of
HA
hydrophilic thiols to
G
was found to be an efficient means to
-helical polypeptides with high degrees
obtain water soluble,

1
7
control over placement of bio-inert segments, i.e. sulfoxide,
of functional modification.
and segments that may promote cell uptake, i.e. sulfonium,18 is
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needed for continued development of multifunctional
Journal Name
This work was supported by the NSF under MVSieNw A1r4tic1le2O3n6li7ne.
biomaterials. While both sulfoxide and sulfonium groups can be Mass Spectrometry Instrumentation DwOaI:s10.m10a3d9/eC8CaCva0i3l0a4b8leK
introduced into
M homopolymers, there is no means to control through the support of Dr. Gregory Khitrov at the University of
placement of these groups as they will be statistically California, Los Angeles Molecular Instrumentation Center –
distributed along the chains. In our experience, due to limited Mass Spectrometry Facility in the Department of Chemistry. We
solubility of
partial oxidation or partial alkylation of
M
in suitable reaction media, precise control over thank Emma Pelegri-O’Day for assistance in setting up thiol-ene
chains is challenging. reactions, and Brian Shao and Professor Hosea Nelson (UCLA)
M
Hence, methodology for facile installation of sulfoxide and for assistance with chiral HPLC studies on Hag amino acids.
sulfonium functionality in discrete segments within
Notes and references
1
(a) J. N. deGruyter, L. R. Malins and P. S. Baran, Biochemistry
2
7
4
017, 56, 3863−3873. (b) T. J. Deming, Chem. Rev. 2016, 116,
86–808. (c) K. Lang and J. W. Chin, Chem. Rev. 2014, 114
764-4806.
,
copolypeptide sequences would be valuable.
Scheme 4. Conformational changes induced by thioether alkylation or
2
3
4
A. Dondoni, Angew. Chem. Int. Ed. 2008, 47, 8995-8997.
S. M. Brosnan and H. Schlaad, Polymer 2014, 55, 391.
oxidation of mEG .
-GHA63
4
To demonstrate the feasibility of such modifications, a block
(a) K. Schlögl and H. Fabitschowitz, Monatsh. Chem. 1954,
HA
85, 1060–1076. (b) R. M. Guinn, A. O. Margot, J. R. Taylor, M.
Schumacher, D. S. Clark and H. W. Blanch, Biopolymers,
copolymer of Met and Hag,
42
M G 19 prepared as described
above, was subjected to a sequence of selective reactions
1
995, 35, 503–512.
HA
(
42
Scheme 5). Hydrophobic, -helical M G 19 was first oxidized
5
(a) J. Sun and H. Schlaad, Macromolecules, 2010, 43, 4445–
O
HA
at Met residues to give the amphiphilic copolymer
M
42
G
19
4
448. (b) K.-S. Krannig and H. Schlaad, J. Amer. Chem. Soc.
containing disordered hydrophilic poly(L-methionine sulfoxide),
2012, 134, 18542-18545.
O
17
6
7
8
H. Tang, L. Yin, H. Lu and J. Cheng, Biomacromolecules 2012,
13, 2609–2615.
M
4
, segments. The thiol mEG SH was then selectively added
to the Hag residues via radical coupling in acidic media, which is
beneficial for thiol-ene conjugation and also prohibits
undesirable reduction of sulfoxides by thiols. The resulting
J. Zhou, P. Chen, C. Deng, F. Meng, R. Cheng and Z. Zhong,
Macromolecules 2013, 46, 6723–6730.
(a) D. S. Poche, S. J. Thibodeaux, V. C. Rucker, I. M. Warner
and W. H. Daly, Macromolecules 1997, 30, 8081–8084. (b) H.
O
HA
copolymer,
M 42mEG4-G 19, now became fully hydrophilic, but
HA
Tang and D. Zhang, Polym. Chem. 2011,
Zhang, H. Lu, Y. Lin and J. Cheng, Macromolecules 2011, 44
641–6644.
W. Wang and P. T. Hammond, Polym. Chem. 2018,
51.
2, 1542–1551. (c) Y.
retained -helical conformations in the mEG4-G domains.

,
The thioether groups in this copolymer were then selectively
alkylated using iodomethane, taking advantage of the
6
9
9, 346–
O
resistance of
conditions.
copolypeptide,
M
residues toward alkylation under these
3
19
The resulting sulfoxide-sulfonium diblock 10 T. J. Deming, Bioconjugate Chem. 2017, 28, 691−700.
11 T. Hayakawa, Y. Kondo and N. Kobayashi, Polym. J. 1975,
38–543.
2 (a) J. C. M. van Hest and D. A. Tirrell, FEBS Lett. 1998, 428
O
HAM
7
,
M
42mEG4-G
19, was water soluble and both
5
segments were now conformationally disordered in water. In
addition to successful selective functional modification of each
copolypeptide domain, the respective thioether modifications
1
,
6
8-70. (b) N. Floyd, B. Vijaykrishnan, J. R. Koeppe and B. G.
Davis, Angew. Chem. 2009, 121, 7398-7942.
also allowed independent conformational switching of each 13 (a) S. C. G. Biagini, S. E. Gibson née Thomas and S. P. Keen. J.
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1
4 J. R. Kramer and T. J. Deming, Biomacromolecules 2010, 11,
3
668 - 3672.
Scheme 5. Synthesis of diblock copolypeptide MO42mEG
-GHAM19 that
15 T. J. Deming, Macromolecules 1999,
32, 4500-4502.
4
contains discrete sulfoxide and sulfonium domains. Percent yields are
total isolated yields of purified copolypeptides.
The efficient polymerization of Hag NCA, good solubility of
GHA allowing preparation of high molecular weight homo- and 17 (a) A. R. Rodriguez, J. R. Kramer and T. J. Deming,
1
6 J. A. Morrow, M. L. Segal, S. Lund-Katz, M. C. Philips, M.
Knapp, B. Rupp and K. H. Weigraber, Biochemistry 2000, 39
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1
Biomacromolecules 2013, 14, 3610-3614. (b) A. L.
Wollenberg, T. M. O’Shea, J. H. Kim, A. Czechanski, L. G.
Reinholdt, M. V. Sofroniew and T. J. Deming, Biomaterials
copolymers, facile modification of Hag residues with thiols, and
ability to further modify the thioether products provide a
number of attractive features supporting utilization of Hag
residues in peptidic materials. Beyond what has been achieved
in previous alkene containing polypeptides, the example
process in Scheme 5 shows how incorporation of Hag residues
into polypeptides can be used to differentially modify discrete
segments in an orthogonal manner and also modulate
polypeptide chain conformations.
2
018, DOI: 10.1016/j.biomaterials.2018.03.057
1
1
8 J. R. Kramer, N. W. Schmidt, K. M. Mayle, D. T. Kamei, G. C. L.
Wong and T. J. Deming, ACS Central Sci. 2015,
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719-1723.
1, 83-88.
,
1
4
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