Rational Design of Programmable Monodisperse Semi-Synthetic Protein Nanomaterials Containing Engineered Disulfide Functionality**

Article abstract of DOI:10.1002/cbic.202100288

The reversible nature of disulfide functionality has been exploited to design intelligent materials such as nanocapsules, micelles, vesicles, inorganic nanoparticles, peptide and nucleic acid nanodevices. Herein, we report a new chemical methodology for t

Full text of DOI:10.1002/cbic.202100288

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ChemBioChem
Rational Design of Programmable Monodisperse Semi-
Synthetic Protein Nanomaterials Containing Engineered
Disulfide Functionality**
[a]
[a, b]
Pavankumar Janardhan Bhandari and Britto S. Sandanaraj*
The reversible nature of disulfide functionality has been
exploited to design intelligent materials such as nanocapsules,
micelles, vesicles, inorganic nanoparticles, peptide and nucleic
acid nanodevices. Herein, we report a new chemical method-
ology for the construction redox-sensitive protein assemblies
using monodisperse facially amphiphilic protein-dendron bio-
conjugates. The disulfide functionality is strategically placed
between the dendron and protein domains. The custom
designed bioconjugates self-assembled into nanoscopic objects
of a defined size dictated by the nature of dendron domain.
The stimuli-responsive behavior of the protein assemblies is
demonstrated using a suitable redox trigger.
Introduction
recent years for de novo design of stimuli-sensitive protein
assemblies which are either completely synthetic or semi-
[11]
Unlike standard covalent bonds, the disulfide bond is one of
the most interesting covalent bonds. Because of this reason,
developing chemical methodology to strategically place disul-
fide bond in both small molecules and macromolecules have
synthetic. Engineering of native globular proteins through a
chemical method yields semi-synthetic proteins with improved
[12]
functions.
However, most of the methods often yield
polydisperse sample that are difficult to characterize and study.
This is in sharp contrast to design of completely synthetic
proteins which are made through genetic engineering/compu-
[1]
gained enormous interest in the recent years. One of the most
important applications of disulfide containing synthetic mole-
cules or macromolecules is in the field of targeted drug
[13]
tational design.
Both the approaches have proven to be
[2]
delivery. The highly reducing environment of cytoplasm of a
living cell (1–10 mM glutathione (GSH)) compared to the
extracellular medium (20–40 μM) is effectively used to design
powerful and have certain limitations and therefore comple-
ment each other. Our group initiated a research program in the
area of de novo design of well-defined semi-synthetic self-
[
3]
[14]
smart drug delivery systems. To date, there are number of
research groups working in this area to develop to disulfide
assembling proteins. To achieve this goal, we invented a new
method named “Micelle-Assisted Protein Labeling (MAPLab)
Technology”. This method provides opportunities to site-
[4]
[5]
containing amphiphilic polymers, inorganic nanoparticles,
[6]
[7]
[8]
dendrimers, virus-like particles, peptide nucleic acids and
specifically install a synthetic hydrophobic group on to a native
[9]
[14a]
nucleic acid nanostructures. However, the engineering of
disulfide bond in these systems is relatively easy as they are
completely synthetic, soluble in organic solvent and therefore
amenable for structural modification.
protein in a predictable manner.
We have demonstrated that
this methodology can be used for labeling of large number of
[
14a]
proteins with various synthetic hydrophobic small molecules,
[14b]
hydrophobic dendrimers
and monodisperse hydrophobic
We have also demonstrated the design of
[14c]
Globular proteins are emerging as nanoscale building blocks
synthetic peptide.
[10]
for the construction of smart drug delivery systems. Com-
pared to other synthetic nanoscale building blocks, globular
proteins are highly complex yet structurally more defined.
Because of these reasons, there is a tremendous interest in the
de novo semi-synthetic proteins containing photo-sensitive
moiety and studied their stimuli-responsive behavior in re-
[14a,d]
sponse to UV-light.
Although, the use of a photosensitive
group as an external trigger provides excellent spatiotemporal
control. However, the phototoxicity associated with the UV light
and its less penetration depth into the skin are the significant
limitations.. On the other hand, use of internal trigger such as
pH, redox and enzyme have been quiet successful for targeted
[
a] P. J. Bhandari, B. S. Sandanaraj
Department of Chemistry
Indian Institute of Science Education and Research – Pune (India)
E-mail: sandanaraj.britto@iiserpune.ac.in
b] B. S. Sandanaraj
Department of Biology
Indian Institute of Science Education and Research – Pune (India)
[15]
delivery of drugs in humans.
[
[
Strategic placement of disulfide functionality in a well-
defined semi-synthetic self-assembling protein is a challenging
task for following reasons; (i) The quest for well-defined system
impose certain restriction on the use of macromolecular
scaffolds, use of hydrophobic linear polymer is not an option
because most of the synthetic polymers are polydisperse.
Therefore, use of dendrimer is the only option as it can be
synthesized as a single chemical entity with polydispersity index
**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.1101/2021.02.05.430015).
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cbic.202100288
This article is part of a Special Collection in collaboration with the Asian
Chemical Biology Initiative (ACBI). Please see our homepage for more articles
in the collection.
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of 1.00. However the challenge is synthesis of a dendrimer is Results
usually multi-step. (ii) Secondly, hydrophobic dendrimer cannot
be directly coupled to protein directly because of solubility
issue and therefore hydrophilic monodisperse linker of appro-
priate length should be attached to the core of the dendrimer,
again synthesis of monodisperse linker increases of number of
synthetic steps overall. (iii) Finally, dendrimer containing mono-
disperse linker should be solubilized in an aqueous medium for
site-specific bioconjugation followed by highly challenging
purification steps and characterization. Because of the above
mentioned challenges, there are only few reports on artificial
Macromolecular design and synthesis of a redox-sensitive
amphiphilic activity-based probe
The macromolecular design has four core structural elements:
(i) hydrophilic globular protein, (ii) monodisperse flexible hydro-
philic linker, (iii) redox-responsive group, and (iv) monodisperse
hydrophobic dendron (Figure 1).
The design strategy for the synthesis of stimuli-responsive
macromolecular probe is shown in Scheme 2a. First, we
synthesized G1, G2, and G3 esters by following a previously
[16]
protein assemblies containing an engineered disulfide bond.
[
14b,d]
Although extremely challenging, it is highly important to
develop a chemical method for design of this class of semi-
synthetic materials because of their applicability in different
reported method with slight modifications (Scheme 1).
Then, the obtained G1 (2a), G2 (3a), and G3 (4a) esters
compounds were subjected to hydrolysis by treatment with
NaOH in ethanol to obtain the corresponding acid derivatives
(5b). The G1-, G2-, and G3- acid derivatives (5b) were then
reacted with 2,2’-disulfanediylbis(ethan-1-ol) in the presence of
EDC and DMAP in DCM to get compound 5c followed by
[1]
[2]
fields such as diagnostics and therapeutics. Towards that
end, herein, we report design and synthesis of redox-sensitive
self-assembling semi-synthetic proteins and their self-assembly
and disassembly behavior in detail.
activation using N,N’-DSC, in the presence of Et N to afford
3
compound 5d. The activated ester 5d was then reacted with
linker amine (6) in the presence of Et N and DMF to obtain
3
compound 5e. Then, the diphosphonate ester 5e was heated
with lithium bromide (LiBr) in DMF to get monophosphonate
Figure 1. Schematic representation of chemical structures of redox-sensitive protein-dendron bioconjugates. These conjugates are composed of protein
blue=chymotrypsin), hydrophilic oligoethylene glycol linker (blue) (CEG=cetylethylene glycol), redox-sensitive disulfide bond (black), and hydrophobic
dendron block (red). Structures of (a) Chy-CEG-SS-G1 (b) Chy-CEG-SS-G2 (c) Chy-CEG-SS-G3.
(
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Scheme 1. Scheme for the synthesis of ester-terminated dendrimers.
ester 5f, which finally on fluorination using DAST in DCM
afforded fluorophosphonate derivative 5g (Scheme 2).
a significant peak for all the bioconjugates was observed with
minor unreacted native protein (Figure 2a).
Next, the purification of these conjugates is performed by
[
14]
using the previously reported procedure by our group. Briefly,
triton X-100 and excess of macromolecular probe in the
reaction mixture were separated by using IEX chromatography.
The unreacted protein and its corresponding conjugate were
separated by using SEC chromatography, where the conjugate
being facially amphiphilic forms higher-order complex driven
via hydrophobic interaction and elutes at an earlier time point,
while the monomeric native protein elutes at a later time point
(Figure S1). MALDI-ToF results of purified conjugates show that
they are extremely pure and devoid of any native protein
(Figure 2b).
Synthesis of redox-sensitive protein-dendron conjugates
The conjugation of redox-sensitive macromolecular probes with
chymotrypsin was attempted in 50 mM phosphate buffer
pH 7.4 by using a micelle-assisted protein labelling (MAPLab)
technology reported by our group. In this approach, the redox-
responsive macromolecular AABPs were solubilized in 10×
critical micelle concentration (CMC) of triton X-100 at room
temperature. Subsequently, obtained homogeneous solution
was then treated with chymotrypsin (Scheme 2b). Then, the
extent of the formation of protein-dendron bioconjugates was
monitored using MALDI-ToF at different time points. After 12 h,
Figure 2. MALDI-ToF characterization redox-sensitive protein-dendron bioconjugates. (a) MALDI-ToF data of the reaction mixtures and (b) purified redox-
responsive protein-dendron bioconjugates, respectively.
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Scheme 2. Scheme for the synthesis of redox-sensitive protein-dendron AABPs and bioconjugates. (a) Scheme for the synthesis of redox-sensitive
macromolecular probes. (b) Scheme for the synthesis of redox-sensitive protein-dendron bioconjugates.
Self-assembly studies of redox-sensitive protein-dendron
bioconjugates
CEG-SS-G1/G2/G3 complexes are found to be 12, 15, and
17 nm, respectively, indicating that the size of redox-sensitive
protein-dendron complexes increases with an increase in the
size of the dendron (Figure 3a). Excited by these results, we
wanted to check how these bioconjugates behave in SEC. To
our surprised, we observed very sharp peak for all three
bioconjugates. In accordance with DLS results, Chy-CEG-SS-G3
eluted earlier (14 mL) followed by Chy-CEG-SS-G2 (15 mL) and
Chy-CEG-SS-G1 (16 mL) (Figure 3b).
Next, we sought to investigate the self-assembling ability of
redox-sensitive protein-dendron conjugates. To do that we
have carried out dynamic-light scattering and size-exclusion
chromatography experiments (Figure 3a and b). All three
bioconjugates exhibited monomodal distribution with very low
poly-dispersity index. The hydrodynamic diameters of the Chy-
Figure 3. Self-assembly studies of redox-sensitive protein-dendron bioconjugates. (a) The hydrodynamic diameter of Chy-CEG-SS-G1/G2/G3 complexes is
determined using DLS. (b) SEC of Chy-CEG-SS-G1/G2/G3 complexes to determine their elution volume.
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Both DLS and SEC studies revealed that the incorporation of
entire complex was disassembled to its consecutive monomers
with 10 eq of DTT (Figure 4a). This experiment reveals that the
10 eq. of DTT is sufficient to completely disassemble the protein
complex Chy-CEG-SS-G1.
Next, in order to check whether the incubation period of
DTT has any effect on disassembly behavior, the bioconjugate
Chy-CEG-SS-G1 complex was incubated with 10 eq of DTT for
the different incubation period. The SEC results reveal that
disulfide moiety does not affect the self-assembly behavior of
protein dendron bioconjugates. In addition, protein complexes
exhibit narrow and monomodal distribution indicative of their
nearly monodisperse character. The DLS and SEC profiles of
protein-dendron conjugates mostly resemble self-assembly
[13]
profiles of natural and synthetic protein cages rather than
[12]
protein-polymer conjugates.
6
0 mins of incubation is sufficient to achieve the complete
disassembly as evident from disappearance of peak at 16 mL
Figure 4b). After establishing the time and the concentration of
(
Dis-assembly studies of redox-sensitive protein-dendron
complexes
DTT required to achieve the complete dis-assembly, we sought
to investigate the dis-assembly behavior of the other two redox
responsive protein complexes, i.e., Chy-CEG-SS-G2/G3. We were
delighted to notice that both Chy-CEG-G2/G3 protein com-
plexes also could be disassembled into respective monomeric
proteins completely upon treatment with 10 eq. of DTT for
about 60 mins. Based on the above experiments, it is evident
that the treatment of 10 eq of DTT for 60 mins is sufficient to
disassemble the Chy-CEG-SS-G1/G2G3 complexes.
Having established the self-assembling behavior of bioconju-
gates, we wanted to test whether the custom-designed protein
nanoassemblies can be programmed to disassemble. Our
hypothesis is upon treatment with DTT, the disulfide function-
ality which connects the hydrophobic dendron to the hydro-
philic linker and the protein would cleave that would convert
facially amphiphilic protein into hydrophilic protein, the loss of
attractive hydrophobic interaction then would lead to disassem-
[14a,d]
bly of protein nanoassemblies.
In order to test this hypothesis, we performed dis-assembly Discussion
studies of Chy-CEG-SS-G1 in 50 mM sodium phosphate pH 7.4.
The Chy-CEG-SS-G1 bioconjugate was treated with the different
equivalent of DTT (10, 20, and 30 eq) for 12 hours. The DTT
treated samples were then subjected to SEC in order to
investigate the disassembly profile. As expected, before DTT
treatment, the protein complex was intact and therefore eluted
earlier (16 mL) compared to native monomeric protein (19 mL).
However, the SEC of DTT incubated samples revealed that the
Rational design of stimuli-responsive drug delivery systems
(SRDDS) provides to opportunity for the targeted delivery of
[17]
drugs to the right location. Among the various stimuli both
[
17]
[18]
[19]
external (temperature,
light,
sound,
etc.) and internal
[20]
[21]
[23]
(pH,
redox,
and enzyme ), redox-trigger is particularly
attractive because of its success in clinics. Previous efforts in
this area have focused on developing a chemical methodology
Figure 4. Dis-assembly profile of redox-sensitive protein-dendron protein bioconjugates; (a) Concentration dependent disassembly studies of Chy-CEG-S-S-G1,
b) Time-dependent dis-assembly studies of Chy-CEG-S-S-G1, (c) Disassembly studies of Chy-CEG-SS-G2 (d) Disassembly studies of Chy-CEG-SS-G3.
(
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for strategic placement of disulfide functionalities in different
with DTT. Although the present system cannot be used for drug
delivery applications because of bio-incompatibility of benzyl-
ether dendron used in this study. However, it lays foundation
for the design of highly defined biocompatible/biodegradable
redox-responsive protein assemblies for future drug delivery
applications. Those studies are under-way in our laboratories
and will be reported in due course.
[4–9]
drug delivery systems.
However, to our knowledge, engi-
neering of disulfide functionality inside the interior of semi-
synthetic protein assemblies have never been attempted. This is
mainly attributed to the challenges associated with the system.
First of all, globular proteins are hard to work with because of
presence of various functional groups therefore it is important
to develop a bioorthogonal reaction which can work in an
aqueous medium. Secondly, the modified protein (semi-
synthetic protein) should be able self-assemble into protein Acknowledgements
assemblies of defined size. Thirdly, installation of disulfide
functionality should not interfere with the self-assembling
ability of semi-synthetic proteins and finally designed protein
assemblies should be responsive to redox trigger.
In this work, we have demonstrated the design and
synthesis of monodisperse macromolecular probes containing
disulfide functionality. The modular approach of our synthetic
methodology allowed us to make suite of probes containing
This work was supported by the DST-SERB Early Career Award to
B. S. S. DST-SERB (ECR/2015/000253) and the DBT grant (BT/
PRI1450/BRB/I0/1370/2015). P. J. B. would like to thank UGC and
CSIR for fellowships. We thank Mr. Yashwant Kumar, Ms. Ruma
Ghosh and Mr. Prashant Badgujar for doing some experiments.
different dendrons. Further, we have used MAPLab Conflict of Interest
[14]
technology for site-specific bioconjugation of chymotrypsin.
The custom designed facially amphiphilic semi-synthetic pro-
teins have found to self-assemble into protein nanoassemblies
of defined size. The size of the protein nanoassemblies can be
systematically tuned by choosing an appropriate dendron. The
above results emphasize that the molecular design is more
tolerant to stimuli-responsive functional group mutations.
Disassembly studies reveal that irrespective of protein
nanoassemblies size and hydrophobic nature, all of them could
be disassembled quantitatively. The above results suggest that
the interiors of protein assemblies are quiet accessible as DTT
can react with the engineered disulfide functionality. The result
obtained from this work also reiterates our previous findings
that the attractive interaction between the hydrophobic groups
We have filed a US patent for the technology disclosed in this
paper.
Keywords: MAPLab Technology · Bioconjugation · Functional
Protein Nanotechnology · Stimuli-Sensitive
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P. J. Bhandari, B. S. Sandanaraj*
– 8
1
Rational Design of Programmable
Monodisperse Semi-Synthetic
Protein Nanomaterials Containing
Engineered Disulfide Functional-
ity
A chemical methodology for the con-
struction redox-sensitive protein as-
semblies using monodisperse facially
amphiphilic protein-dendron biocon-
jugates is reported. The custom
designed bioconjugates self-
assembled into nanoscopic objects of
a defined size dictated by the nature
of dendron domain.