Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water

Article abstract of DOI:10.1002/anie.202106458

We report the functionalization of cysteine residues with lipophilic alkynes bearing a silyl group or an alkyl chain using amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions were carried out in buffer (pH 6 to 9), without organic co-solvent or removal of oxygen, either at 37 °C or room temperature. The transformation led to a significant increase of peptide lipophilicity and worked for aromatic thiols, homocysteine, cysteine, and peptides containing 4 to 18 amino acids. His₆-Cys-Ubiquitin was also alkynylated under physiological conditions. Under acidic conditions, the thioalkynes were converted into thioesters, which could be cleaved in the presence of hydroxylamine.

Full text of DOI:10.1002/anie.202106458

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Accepted Article
Title: Amphiphilic Iodine(III) Reagents for the Lipophilization of
Peptides in Water
Authors: Abhaya Kumar Mishra, Romain Tessier, Durga Prasad Hari,
and Jerome Waser
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Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water
Abhaya Kumar Mishra,† Romain Tessier,† Durga Prasad Hari and Jerome Waser*[a]
together with organic co-solvents, due to the low solubility of the
lipophilic reagents, which can be an issue in presence of sensitive
biomolecules. There are only few reagents for cysteine
functionalization that are fully water-soluble,[14] and only reagent
E was reported for the specific case of lipidation, based on the
formation of labile disulfide bridges.[14a]
Abstract: We report the functionalization of cysteine residues with
lipophilic alkynes bearing silyl groups and alkyl chains using
amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions
were carried out in buffer (pH 6 to 9), without organic co-solvent or
removal of oxygen, either at 37 °C or room temperature. The
transformation led to a significant increase of peptide lipophilicity and
worked for aromatic thiols, homocysteine, cysteine and peptides
containing
4 to 18 amino acids. His6-Cys-Ubiquitin was also
alkynylated under physiological conditions. Under acidic conditions,
the thioalkynes were converted into thioesters, which could be
cleaved in the presence of hydroxylamine.
Since the use of insulin in the treatment of diabetes,[1] the
importance of peptide-based drugs has constantly increased.[2]
However, the high polarity and low stability of natural peptides
result in unfavorable pharmacological properties, requiring
chemical modifications.[3] An adequate lipophilicity is essential to
control the ADMET properties (absorption, distribution,
metabolism, elimination and toxicology),[4] and the lipidation of
peptides has proved to be effective in this regard.[5] The lipidation
of proteins, through post-translational modifications (PTMs), is an
essential process to control the properties and localization of
biomolecules in the cell.[6] Lipopeptides have also found
numerous applications in material sciences.[7]
Peptides and proteins containing nucleophilic residues are often
functionalized with electrophilic reagents.[8] Considering their low
abundance and high nucleophilicity, cysteines are targets of
choice.[9] To achieve lipidation, naturally occurring palmitoylation
and prenylation have been the focus of most research.[10] Due to
the low stability of thioesters and the importance of permanent
lipidation in multiple applications, chemists have recently focused
on more stable natural lipids (Figure 1a).[4,5] Brimble and co-
workers reported the photoinitiated coupling of cysteines with
vinyl palmitate A via a thiol-ene process.[11] Breinbauer and co-
workers developed
a palladium-catalyzed geranylation of
cysteine residues using carbonate reagent B.[12] Reports on stable
non-natural modifications of cysteine under mild physiological
conditions remain scarce (Figure 1b).[9d] Müller, Wessig and co-
workers used maleimide derivatives C and D for the recruitment
of thiol-containing peptides into the cell membrane.[13] Many
reported lipidation processes use highly reactive reagents
Figure 1. a) Chemical methods for stable natural lipidation. b) Reported
reagents for non-natural lipidation. c) EBX reagents for cysteine labelling. d)
This work: amphiphilic reagents for non-natural lipidation under physiological
conditions. DMPA = 2,2-dimethoxy-2-phenylacetophenone, NMP = N-methyl-2-
pyrrolidone, BIPHEPHOS = 6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-
biphenyl-2,2′ -diyl)bis(oxy)]bis(di-benzo[d,f][1,3,2]dioxaphosphepin), TIPS =
triisopropylsilyl, TMS = trimethylsilyl.
[a]
Dr. A. K. Mishra, Dr. R. Tessier, Dr. D. P. Hari, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
E-mail: jerome.waser@epfl.ch
Our group previously investigated ethynylbenziodoxolone (EBX)
reagents for the alkynylation of thiols (Figure 1c).[15] The non-
water-soluble reagent triisopropylsilylethynyl-benziodoxolone
(TIPS-EBX, 1) was used in organic solvents.[15a,16] Less lipophilic
alkyl reagents, such as JW-RF-010 (2) gave alkynylated thiols,
hypervalent iodine vinylbenziodoxolone (VBX) addition products
Dr. R. Tessier
Present address: Department of Chemical Biology
Max Planck Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
†These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.202106458
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or a mixture of both depending on the cysteine reactivity and the
reaction conditions.[15b-d] Finally, trimethysilylated reagents such
as JW-RT-01 (3) were deprotected under physiological
conditions.[15e]
Table 1. Optimization of the reaction conditions with TIPS-EBX-SO3K (4a) and
glutathione (6)
The importance of lipo-peptides and -proteins, combined with the
lack of lipidation methods in absence of organic solvents and the
reactivity of EBXs towards thiols, motivated us to design water-
soluble amphiphilic-EBXs. Herein, we report the synthesis of
sulfonylated EBXs 4a and 4b and their application for the
lipophilization of unprotected peptides and proteins under
physiological conditions (Figure 1d). Under acidic conditions, the
obtained thiolakynes could be converted to cleavable thioesters.
Entry
Reaction conditions[a]
6a Yield (%)[b]
1
10 mM Tris, pH 7.4, rt, 6 h
10 mM Tris, pH 7.4, rt, 16 h
10 mM Tris, pH 7.4, 37 °C, 6 h
40 mM Tris, pH 7.4, 37 °C, 6 h
80 mM Tris, pH 7.4, 37 °C, 6 h
200 mM Tris, pH 7.4, 37 °C, 6 h
10 mM Tris, pH 7.0, 37 °C, 6
10 mM Tris, pH 8.2, 37 °C, 6 h
10 mM Tris, pH 9.0, 37 °C, 6 h
10 mM Tris, pH 6.0, 37 °C, 6 h
Water, 37 °C, 6 h
47
83
95
84
48
24
93
94
93
54
90
2
3
4
5
6
Among the approaches to access water-soluble hypervalent
iodine reagents,[17] we focused on sulfonylated derivatives[18]
because the iodine precursor 2-iodo-5-potassium sulfonate (5a)
is easily accessible (see SI)[19] and the sulfonate group ensures
good solubility in water at a broad range of pHs. 5a was oxidized
to 5b by NaIO4 in 85% yield. Installation of the alkyne on 5b was
achieved by using a large excess of Lewis acid. We first prepared
TIPS-EBX-SO3M (4a),[20] as silylated reagents are known to
exclusively give alkynylation products.[15] A slightly modified
procedure (BF3OEt2 instead of TMSOTf as Lewis acid) then
allowed us to access the alkyl reagent C14H29-EBX-SO3M (4b).
Gratifyingly, 4a displayed a more than fifty fold increased solubility
in water compared to TIPS-EBX (1) (0.46 for 4a vs < 10 mg/mL
for 1) and 4b was also well soluble (0.45 g/mL).
7
8
9
10
11
[a] Labeling condition: 16.0 µmol scale in 1.6 mL of non-degassed buffer. [b]
Relative ratio of 6a and disulfide based on HPLC-UV at 214 nm.
Scheme 2. Optimized conditions for the reaction of 4b with glutathione (6).
HPLC-MS yield is indicated. [a] Isolated yield. [b] Calibrated yield.
Scheme 1. Synthesis of TIPS-EBX-SO3M (4a) and C14H29-EBX-SO3M (4b). a)
NaIO4 (1.05 equiv.), 30% aq. AcOH (v/v), reflux, 4 h; b) TMSOTf (3.0 equiv.),
pyridine (6.0 equiv.), DCE, 40 °C, 22 h; c) BF3Et2O (3.0 equiv.), pyridine (1.1
equiv.), CH3CN, rt, 24 h.
With 4-bromothiophenol (7), alkynylation product 7a was obtained
in 72% isolated yield with 4a (Scheme 3a). Naphthalene-2-thiol
(8) gave 68% yield of 8a. Both aromatic thiols 7 and 8 did not
convert to alkynes 7b and 8b using 4b. Nevertheless, 8b could
We then examined the alkynylation of glutathione (6, GSH) in
buffer (Table 1). In 10 mM Tris buffer at pH 7.4 at rt,[15] S-
alkynylated product 6a was obtained in 47% yield in 6 h (entry
1).[21] After 16 h, the yield was improved to 83% (entry 2). At 37 °C,
95% yield could be obtained in 6 h (entry 3). With gradual increase
of the buffer concentration, the yield decreased from 83% to 24%
(entries 4 to 6). Surprisingly, the yield was almost unchanged from
pH 7.0 to 9.0 (entries 7-9). Even at pH 6.0, 54% of the product
was obtained (entry 10). This is unusual for cysteine
functionalization, which proceeds normally better under basic
conditions. Other buffers led to lower yields (see SI). The reaction
proceeded also in pure water (entry 11). The reaction conditions
had to be optimized again for reagent 4b, due to increased
formation of side products (see SI, Table S2). Best results were
obtained with a 200 mM Tris buffer at pH 8.0 (Scheme 2).
According to our experience with alkyl-EBXs, we expected to
obtain VBX product 6c.[15d] However, a mixture of alkynylated (6b),
as major product, and VBX (6c), as minor product, was obtained.
be obtained in 29% yield using
a 100 mM PB buffer.
Homocysteine (9) gave 9a in 95% HPLC-MS yield. Reaction with
4b gave 66% of alkyne 9b together with 34% of VBX 9c. The
reaction of unprotected cysteine (10) with 4a and 4b also
proceeded well. After 6 h with 4b, only 10b was observed. With
N-acylated peptide 11, the alkynylation gave 82% of 11a (79%
calibrated yield and 35% isolated, Scheme 3b).[21] Using EBX 4b,
11b was obtained in 82% yield and 18% VBX 11c was observed
by HPLC. N-terminus unprotected hexapeptides 12 and 13
underwent alkynylation efficiently with both reagents. The
reaction was selective for cysteine in presence of other
nucleophilic amino acids such as serine, threonine, aspartic acid
or lysine (peptides 14-18). Larger peptides 19-21 (15 to 18-mer)
were then investigated (Scheme 3c). Peptide 19 gave 19a in 76%
yield. Alkyne 19b was obtained in 50% yield when using a 100
mM PB buffer. Both reagents 4a and 4b worked well with peptides
20 and 21 bearing nucleophilic side chains such as lysine,
tryptophan, tyrosine, serine, threonine or glutamic acid.
2
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10.1002/anie.202106458
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Scheme 3. Scope of the alkynylation reaction for a) non-peptides, b) tetra- and hexa-peptides and c) larger peptides. All the reactions were performed in 0.5 to 8.0
µmol scale at 10 mM concentration. Freshly prepared buffer was used without removing oxygen. Yields: relative ratio based on reverse phase HPLC-MS
chromatogram unless stated otherwise. [a] Isolated yield. [b] Reactions were performed in 100 mM PB buffer at pH 8.0 at rt. [c] Calibrated yield.
3
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We then turned our attention to biologically relevant peptides
(Scheme 4): Leu55-His63 fragment 22 derived from human serum
albumin, Trp554-Ala566 fragment 23 derived from the hepatitis C
virus (HCV) envelope glycoprotein E2[22] and Phe32-Thr40
fragment 24 derived from the human immunodeficiency virus
(HIV) tat protein.[23] Peptides 22 and 23 were successfully
alkynylated with both reagents. With peptide 24 containing two
cysteines, bisalkynylated product 24a was obtained in 57% yield
with 6 equivalents of 4a. Cysteine-containing modified His6-Cys-
ubiquitin (25)[15d] was also alkynylated efficiently with 4a. However,
the use of reagent 4b led to a complex mixture of products.
substituted thioester 18aa reacts only very slowly under these
conditions, probably due to the sterically hindered TIPS group.
Nevertheless, treatment with
a KF solution followed by
hydroxylamine also allowed to cleave this thioester with 90%
conversion. Taken together, our work therefore gives access to
lipophilic peptide derivatives modifiable/cleavable under different
conditions, which can be exploited depending on the desired
application.
Scheme 4. Alkynylation of peptides 22-24 and His6-Cys-ubiquitin (25). Reaction
conditions: for 22a and 23a: 4a (1.5 equiv.),10 mM Tris pH 7.4, 37 °C, for 22b
and 23b: 4b (1.2 equiv.), 200 mM Tris buffer pH 8.0, rt. [a] isolated yield. [b]
calibrated yield. [c] 4 and [d] 6 equiv. of 4a was used in 10 mM Tris pH 7.4 at
37 °C, 5 mM. [e] Reaction was performed at 300 M concentration.
Scheme 5. a) Access to thioesters from unprotected peptides in one pot via
thioalkynes and b) Cleavage of the thioesters. See Supporting Information for
detailed reaction conditions. [a] VBXs remain untouched under these reaction
conditions. [b] isolated yield. [c] calibrated yield.
A significant increase of retention time in RP-HPLC was observed
for all alkynylated peptides, indicating qualitatively higher
lipophilicity. For example, the retention time of peptide 11 shifted
from 5.8 to 13.6 min for 11a and 20.2 min for 11b (See SI). The
partition coefficient (LogP) of product 11a was determined to be
1.53 compared with -1.43 for 11.[24]
In summary, we have synthesized amphiphilic EBX hypervalent
iodine reagents, which were employed for the selective
lipophilization of cysteine under physiological conditions (pH 7.4-
8.0, from room temperature to 37 °C in buffers without organic co-
solvents). Aromatic thiols, homocysteine, cysteine and
unprotected tetra- and hexapeptides were successfully
alkynylated. Larger peptides (15 – 18-mers) and one protein
(His6-Cys-Ubiquitin (25)) could also be selectively functionalized.
Both retention time in reverse phase HPLC and LogP
determination showed a significant increase of lipophilicity for the
modified peptides, and the obtained thioalkynes could be
converted into thioesters under acidic conditions. The thioesters
could be easily cleaved using either hydroxylamine or a
fluoride/hydroxylamine mixture.
The obtained thioalkynes constitute a new type of lipophilic
compounds lacking the electrophilic carbonyl group present in
natural palmitoylated peptides, which is required for their
hydrolysis. In presence of trifluoroacetic acid (TFA), clean
hydration to give thioesters was observed (Scheme 5a). This
hydration can be performed in a one pot protocol with silylated
and alkylated alkynes on both small and larger peptides to give
thioesters such as 11aa-bb, 17aa-bb, 18aa and 23aa-bb in 58-
82% yield. 11bb, 17bb and 23bb are then natural palmitoylated
products. The VBX products 11c and 23c did not react under
these acidic conditions. Numerous enzymatic and chemical
methods have been reported for the cleavage of palmitoyl groups
on cysteine.[25] Indeed, when peptide 17bb was submitted to a 1
M solution of hydroxylamine, quantitative cleavage of the
thioester was observed (Scheme 5b). In contrast, the silyl
Acknowledgements
This work is supported by the European Research Council (ERC
Consolidator Grant SeleCHEM No. 771170) and EPFL. We thank
4
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Nora Guidotti from the group of Prof. Beat Fierz at ISIC at EPFL
for a gift of His6-Cys-ubiquitin (25).
Keywords: • Amphiphilic reagents• Hypervalent Iodine •
Lipidation • Lipopeptide • Ubiquitin
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In Water! Amphiphilic hypervalent iodine reagents enable the alkynylation of cysteine residues in peptides with lipophilic groups in
water. The reaction proceeds in neutral standard buffers with high efficiency for a broad range of peptides and one protein. The
thioalkynes can be converted into cleavable thioesters under acidic conditions.
Institute and/or researcher Twitter usernames: @EPFL_CHEM_Tweet @LcsoLab
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