Data-Driven Identification of Hydrogen Sulfide Scavengers

Article abstract of DOI:10.1002/anie.201905580

Hydrogen sulfide (H₂S) is an important signaling molecule whose up- and down-regulation have specific biological consequences. Although significant advances in H₂S up-regulation, by the development of H₂S donors, have been achieved in recent years, precise H₂S down-regulation is still challenging. The lack of potent/specific inhibitors for H₂S-producing enzymes contributes to this problem. We expect the development of H₂S scavengers is an alternative approach to address this problem. Since chemical sensors and scavengers of H₂S share the same criteria, we constructed a H₂S sensor database, which summarizes key parameters of reported sensors. Data-driven analysis led to the selection of 30 potential compounds. Further evaluation of these compounds identified a group of promising scavengers, based on the sulfonyl azide template. The efficiency of these scavengers in in vitro and in vivo experiments was demonstrated.

Full text of DOI:10.1002/anie.201905580

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Accepted Article
Title: Data-Driven Identification of Hydrogen Sulfide Scavengers
Authors: Ming Xian, Chun-tao Yang, Yingying Wang, Eizo Marutani,
Tomoaki Ida, Xiang Ni, Shi Xu, Wei Chen, Hui Zhang, Takaaki
Akaike, and Fumito Ichinose
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905580
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10.1002/anie.201905580
Angewandte Chemie International Edition
COMMUNICATION
Data-Driven Identification of Hydrogen Sulfide Scavengers
Chun-tao Yang,† Yingying Wang,† Eizo Marutani, Tomoaki Ida, Xiang Ni, Shi Xu, Wei Chen, Hui
Zhang, Takaaki Akaike, Fumito Ichinose, and Ming Xian*
Abstract: Hydrogen sulfide (H2S) is an important signalling molecule
whose up- and down-regulation have specific biological
consequences. Although significant advances in H2S up-regulation,
via the development of H2S donors, have been achieved in recent
years, precise H2S down-regulation is still challenging. The lack of
potent/specific inhibitors for H2S-producing enzymes contributes to
this problem. We expect the development of H2S scavengers is an
alternative approach to address this problem. Since H2S’s chemical
sensors and scavengers share the same criteria, we constructed a
H2S sensor database, which summarizes key parameters of reported
sensors. Data-driven analysis led to the selection of 30 potential
compounds. Further evaluation of these compounds identified a group
of promising scavengers, based on the sulfonyl azide template. The
efficiency of these scavengers in in vitro and in vivo experiments was
demonstrated.
ischemia, cancer, and diabetes.[5] Therefore, it is important to
explore chemical approaches to decrease endogenous H2S
contents while this is much less developed. To this end, an
obvious approach is to explore inhibitors for H2S-producing
enzymes. Although some efforts have been put into this line of
research, currently available inhibitors are still far from ideal.[6]
These inhibitors (aminooxyacetic acid, propargylglycine, -cyano-
L-alanine, aminoethoxyvinyl glycine, cystathionine’s -NHNH2/-
ONH2/-NHOH analogs, etc.) are known to have limitations like
poor bioavailability, low specificity, and modest potency. As H2S-
producing enzymes are ubiquitously involved in sulfur
metabolisms, interfering enzyme activities may lead to unwanted
side effects, which is a generic problem of inhibitors. Another
significant challenge with H2S research is that H2S is always in
equilibrium with its closely related sulfur species including H2Sn
and persulfides. This further complicates the task of decreasing
endogenous H2S. It has also been shown that enzymes like
CARS and 3MST primarily produce Cys-persulfide or H2Sn, with
H2S being their subsequent metabolite. It is therefore extremely
difficult, if not impossible, to only control endogenous H2S levels
via inhibition of the enzymes.
We envisioned that an alternative approach to decrease
endogenous H2S is to develop scavengers. Ideally scavengers
should specifically and rapidly react with H2S, therefore, only
eliminating H2S functions in certain biological systems. By doing
so, interference with other necessary enzyme activities unrelated
to H2S could be avoided. Another advantage of this approach is
that scavengers can be conjugated with specific targeting
molecules and delivered to specific cellular locations, thereby
achieving targeted clearance. This provides a convenient way to
interpret outcomes of H2S elimination in certain systems. While
this sounds a simple idea, to the best of our knowledge, H2S
scavengers for the aforementioned purposes have not been
explored. This ‘chemical knockdown’ concept is an interesting
direction for chemical biology as chemical reagents that can
specifically remove biologically important molecules should find
wide applications. For example, quinone methide has been used
as a scavenger for glutathione while its specificity is still
problematic.[7] It should be noted H2S scavengers are well-known
in industrial settings as the removal of H2S in industrial processes
has been extensively studied.[8] Materials like metallic oxide,
alkanolamines, and metal carboxylates/chelates have been used
as H2S scavengers and obviously these cannot be applied into
biological systems for our purposes. Moreover, several
compounds are used clinically as antidotes for H2S poisoning, but
their specificity and applications for H2S-related pathologies have
not been studies. For example, hydroxocobalamin (HC) has been
investigated as an antidote for H2S poisoning, but it also
scavenges cyanide, NO, CO, and ROS,[9] indicating its non-
specificity.
As an important signaling molecule, the production of H2S in
mammals has been attributed to enzymes including cystathionine
-synthase
(CBS),
cystathionine
-lyase
(CSE),
3-
mercaptopyruvate sulfur-transferase (3MST), and cysteinyl-tRNA
synthetase (CARS).[1] While the actual chemical identity of the
signaling molecule produced by these enzymes remains
controversial (H2S vs its closely related sulfur species), we will
focus our discussion on H2S for the purpose of this manuscript.
Current knowledge indicates that dysregulated H2S levels are
linked to many pathological processes like cancer, inflammation,
hypertension, etc.[2] Consequently, compounds that can be used
to precisely regulate H2S concentrations (up and down) are
important research tools as well as potential therapeutic agents.
In this regard, the studies of H2S releasing compounds (or donors)
have attracted considerable attention recently.[3] A large number
of donors with different structures (phosphorthioates, N-
mercapton derivatives, thiocarbamates, acyl disulfides,
thioamides, gem-dithiols, etc.) have been developed, along with
various triggering mechanisms (thiol-, photo-, pH-, ROS-, or
enzyme-triggered).[4] The availability of these molecules has
advanced our understanding of H2S in biology.
On the other hand, over-production of H2S is also known to
cause adverse effects in pathological states, like cerebral
[]
C.T. Yang and H. Zhang
Affiliated Cancer Hospital & Institute of Guangzhou Medical
University, Guangzhou 510095, China
[*]
Y. Wang, X. Ni, S. Xu, W. Chen, and Prof. Dr. M. Xian
Dept. Chemistry, Washington State University
WA 99164, US mxian@wsu.edu
Dr. E. Marutani and Prof. F. Ichinose
Dept. Anesthesia, Critical Care and Pain Medicine, Massachusetts
General Hospital/Harvard Medical School, Boston, MA 02114, USA
Dr. T. Ida and Prof. T. Akaike
Department of Environmental Medicine and Molecular Toxicology,
Tohoku University, Sendai 980-8575, Japan
CTY and YW contributed equally
†
Supporting information is given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905580
Angewandte Chemie International Edition
COMMUNICATION
Type 2
Type
1
O
O
With these considerations in mind, we set to explore potent
H2S scavengers. The criteria of ‘ideal’ scavengers are: 1) highly
reactive to H2S (should react with H2S rapidly in minutes not in
hours), 2) highly selective to H2S (should only react with H2S, not
react with other species like ROS, RNS, etc), 3) negligible
biological activity (scavengers and their H2S reaction products
should have no or low biological activities), and 4) structural
flexibility for modifications (like introducing targeting molecules).
In our opinion, these criteria are the same as the criteria for H2S
fluorescent sensors, which is a well-studied field.[10] We have
recently constructed an online database on H2S fluorescent
sensors (http://sensor.eecs.wsu.edu/index/). It covers all reported
sensors with key parameters (structure, solubility, cytotoxicity,
response rate, excitation/emission wavelengths, selectivity, etc).
We believe the most critical parameter of effective scavengers is
their reactivity to H2S, which is determined by the reaction site.
Therefore, we analyzed the time needed for the sensors to
complete the reaction and group them based on their reaction site.
Figure 1 shows the results of 8 major types (each has >5 sensors):
1) benzoxadiazole based sensors, 2) aryl nitro based sensors, 3)
aryl azide based sensors, 4) 2,4-dinitrobenzene based sensors,
5) aldehyde based sensors, 6) disulfide based sensors, 7) sulfonyl
azide based sensors, and 8) indolium based sensors. The
structures of representative sensors in these types are shown in
Figure S1 (Supporting Information). It should be noted that we did
not include metal-sulfide precipitation based sensors as we did
not expect such a reaction would be suitable for scavengers due
to inherent toxicity of metal-containing compounds.
O
O
O
O
N
N3
NO2 HN
N
NO2
N
N
N
N
O
O
SS1
SS2
NO2
NO2
SS4
SS3
Type
3
O
O
Type
PhO
O2N
4
O
N
N3
N
NO2
S
N3
O
O
N3
SS9
SS6
SS8
SS7
N3
SS5
O
O
Type
6
Type
5
O
O
O
O
Ph
Se
O
O
Se
O
O
O
O
O
S
O
O
S
O
S
S
CHO
SS10
SS12
Py
SS11
Py
O
O
O
O
S
O
O
Se
O
O
O
Py
SS13
Se
Se
S
S
SS14
Py
Py
Type
7
NO2
N
CO2H
O
O
S O
N3
SS21
O
S
O
N3
O
S
O
O
S
O
O
S
O
O
S
O
N3
N3
SS20
N3
N3
N3
SS18
SS17
SS19
SS16
SS15
Type
8
S
N
N
N
N
N
O
O
SS24
SS22
SS23
Type 10
NC CO2Et
Type
9
Type 11
Br
NC
CO2Et
O
OEt
O
OPh
NC
CO2Et
S
S
CO2Ph
SS27
CO2Me
SS28
CO2
SS29
H
SS26
SS30
SS25
Fig. 2 Structures of scavenger candidates
These compounds’ scavenging ability was evaluated by the
following protocol: H2S solution (100 μM) was freshly prepared in
PBS and placed in a sealed vial. H2S concentration was
continuously monitored by a Unisense H2S microsensor. As
shown in Figure S2-a, if no scavenger was added, a steady H2S
concentration was maintained. When 100 μM CuSO4 was
added,a sharp concentration drop was noted (Fig.S2-b), serving
as a positive control to demonstrate this method could monitor
H2S concentration changes. With effective scavengers, rapid H2S
concentration decreases were observed (Fig.3-a) while with
ineffective scavengers slow or sometimes negligible H2S
concentration decreases were observed (Fig.3-b). To compare
the efficiency of scavengers, T1/2 (the time needed for the
concentration dropped to 50%) was recorded and summarized in
Figure S3. If T1/2>5 min, the scavengers were considered
ineffective. For effective scavengers (T1/2<5 min), we also tested
the interference of 500 μM cysteine. This is because H2S-reaction
sites are possibly reactive to biothiols, albeit at slower rates. We
wanted to make sure the scavengers won’t be consumed by thiols.
As shown in Fig.S3, from 30 candidates, we found 11 promising
scavengers (SS2-3, SS10, SS13, SS15-20, and SS22) which
could rapidly remove H2S and their scavenging ability was not
significantly affected by cysteine. This high success rate
demonstrates that the H2S sensor database is a useful starting
point for scavenger identification.
Fig. 1 Response time of reported H2S sensors. Sensors were divided into 8
types. The time was analyzed and presented as mean±SE.
As can be seen from Figure 1, type 1-3 sensors showed
relatively long reaction times (~60 min) while type 5-8 sensors
showed much faster response (<10 min). Based on these analysis,
30 compounds were selected (Fig. 2). In addition to fast reaction
rates, the following criteria were also considered: a) the reported
selectivity for H2S vs biothiols was high (>100 folds), b) the sensor
has been used in cells, indicating low toxicity. We also attempted
to cover structural diversity so some representative sensor
templates were also included even their response rates or
selectivity were not that high. In addition, selected structures
representing miscellaneous sensors (type 9-11, reported sensors
are <4 in each) were also included. More importantly, as our goal
was to identify H2S-removling molecules, the fluorescent
component was unnecessary. Therefore, for some sensors only
their H2S-reacting templates were used. Notably the properties of
reported sensors were tested under different conditions from one
to another, sometimes even in high concentrations of organic
solvents. It is hard to compare sensors across the broad. To
systematically compare these sensors-derived scavengers the
candidates were evaluated in pure buffers for their efficacy.
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10.1002/anie.201905580
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solutions were treated with different concentrations of
scavenger (using SS19 as an example). At different time points
a
–SH trapping electrophile, β-(4-hydroxyphenyl)ethyl
iodoacetamide (HPE-IAM) or monobromobimane (MBB) was
used to capture the remaining H2S and the product was
quantified by LC-MS/MS. As shown in Figure 5-a/b, both HPE-
IAM and MBB assays demonstrated that SS19 could completely
remove H2S in a few min. Moreover, SS19 was also tested in an
enzymatic sulfide generation system. We have previously
demonstrated that CARS can convert cysteine to Cys-
persulfide[1b] and in this process H2S is formed via reductive
decomposition of persulfides. Thus, CARS (E. coli recombinant,
100 µg/mL) was incubated with Cys (100 µM) for 10 min. Next
SS19 was applied. H2S contents were then analyzed by HPE-
IAM assay. Again we observed time- and concentration-
dependent H2S clearance (Fig. 5c); whereas Cys-persulfide was
also quenched, but to a lower degree (Fig. 5d). The removal of
H2S in this system appeared to be slower than using H2S
directly. This could be due to the fact that the enzymatic
production of H2S is a slow but continuous process.
Fig. 3 Representative H2S removing profiles. a) a fast scavenger SS16 (100
μM), d) a slow scavenger SS5 (100 μM) was added into H2S solution
To further validate these promising molecules, we tested
their H2S-scavenging ability in more complex environments.
Briefly, 200 μM H2S solution was prepared in cell culture medium
with 10% FBS and treated with the scavengers (200 μM). After
incubation for 1 h, the remaining H2S was measured by H2S gas
trapping followed by methylene blue assay.[11] As shown in Figure
4, SS15-20 and SS22 effectively reduced H2S content, while the
scavenging ability of SS2, SS3, SS10 and SS13 were somewhat
diminished. It is possible that other amino acids or proteins in the
medium compete with H2S to react, thereby decreased their
efficacy.
We also analyzed the reaction between sulfonyl azide and
H2S in buffers (Scheme S1). It was found that elemental sulfur
S8 and sulfonamide were the products. It should be noted that
the reaction mechanism between arylazide and H2S was studied
previously[13] and the transient H2S2 was found to be the
intermediate which eventually formed S8. The reaction of
sulfonyl azides was a lot faster than that of arylazides, due to
the stronger electron withdrawing property of sulfonyl compared
to aryl. We viewed the conversion of H2S to S8 as a unique and
potential useful way, which not only converts highly reactive and
bioactive H2S to an inert species (S8), but also produces a
reserve pool of H2S for future uses.
The efficiency of sulfonyl azide based scavengers in
removing H2S in cellular systems was further validated by
fluorescence assays. For example, the addition of H2S (100 μM)
into cell lysate significantly enhanced the fluorescence intensity
of a specific fluorescent probe WSP5, while a dose-dependent
attenuation of the fluorescence intensity was observed with
adding SS17 (Fig. S6). Cell imaging also showed that
intracellular H2S was effectively reduced by the pretreatment of
SS17 (Fig. S7).
Fig. 4 Measurements of trapped H2S with methylene blue assay. H2S (200
μM) in cell culture medium with 10% FBS was treated with scavengers in a 20
mL vial with a gas trapping EP tube inside.
With these compounds (SS15-20, SS22) being narrowed
down as possible scavengers, we tested their toxicity in several
cell lines including HeLa, SNU398, etc. As these structures were
based on known sensors that had been used in cells, we did not
expect to see significant toxicity. In our studies, sulfonyl azides
(SS15-20) showed negligible toxicity but SS22 was found to be
toxic (Fig. S5). Therefore, sulfonyl azides were identified to be
the most promising scavengers.[12]
To demonstrate the scavengers can attenuate H2S‘s
biological
effects,
two
in
vitro
models
(cancer
growth/inflammation) were employed. Reportedly H2S could
induce cancer (liver, tongue, etc) growth, especially in cells with
high H2S levels.[14] In the first model, we tested the influence of
the scavenger on H2S-induced growth of liver cancer SNU398
cells. As shown in Figure 6a, a 24 h-exposure to H2S
significantly enhanced cell growth. However, pretreatment with
SS17 for 30 min before H2S exposure markedly attenuated the
effects of H2S. In the second model, LPS could trigger
inflammation in raw 264.7 macrophages, evidenced by
increased TNF-α secretion. This effect could be markedly
reduced by H2S, indicating its anti-inflammatory effect.[15]
However, when cells were preconditioned with SS17, H2S-
induced anti-inflammation was obviously attenuated (Fig. 6b).
We also tested the sulfonamide product of SS17 in these cell
models and it did not affect the responses of cells (Fig. S8 and
Fig. 5 a) H2S-HPE-IAM adduct con. in SS19 treated H2S solutions. b) H2S-
MBB adduct con. in SS19 treated H2S solutions. c) H2S-HPE-IAM adduct con.
in CARS system. d) Cys-persulfie-HPE-IAM con. in CARS system.
We further demonstrated the efficiency of sulfonyl azides
using our established electrophile-trapping assays with LC-
MS/MS identification.[1b] Briefly, in Tris-HCl buffers 10 µM H2S
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10.1002/anie.201905580
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COMMUNICATION
Fig. S9). These results confirmed the effects of the scavenger in
eliminating H2S-induced biological functions.
and they likely work collectively to exert the functions of H2S (or
H2Sn and persulfides). In fact, we observed that sulfonyl azides
reacted with cysteine persulfide, albeit at markedly slower rates
compared to its reaction with H2S (Fig. 5d). Because they are in
equilibrium, even
a truly selective H2S scavenger would
decrease and eventually eliminate all these sulfur species in a
given system. We believe complete removal of these
nucleophilic –SH containing reactive sulfur species would
benefit the study of biological effects of H2S and be ideal for
antidotes for “H2S” poisoning.
In conclusion, the identification of potent H2S scavengers is
an urgent and unmet need in the field. In this work we
systematically analyzed published data on H2S fluorescence
sensors, and selected/tested a series of candidates being the
possible scavengers. This data-driven approach allowed us to
quickly discover sulfonyl azides as very promising scavengers.
Their H2S scavenging capabilities were demonstrated in buffers,
enzymatic systems, and cellular environments. We also
validated the scavengers in H2S-induced cell proliferation and
anti-inflammation models, as well as in vivo H2S intoxication
model in mice. We expect these highly effective scavengers will
be not only useful tools in clarifying the biological roles of H2S,
but also potential therapeutic agents, such as a new class of
antidotes for H2S poisoning.
Fig. 6 (a) Effects of SS17 on H2S-induced SNU398 cell growth. Cells were
treated with H2S for 24 h w/ or w/o SS17 preconditioning. (b) Effects of SS17
on anti-inflammation of H2S. Raw 264.7 cells were pretreated with 100 μM
H2S or/and 100 μM SS17 for 30 min, followed by stimulation of 1 mg/L LPS
for 24 h. Data are shown as mean±SE. n=4.
To determine efficacy of the scavengers in vivo, we
examined whether a sulfonyl azide scavenger (SS20) could
rescue mice from H2S intoxication. H2S is a highly neurotoxic
gas and survivors of acute H2S exposure may develop long-
term, often devastating neurological sequelae including
permanent vegetative states, memory loss, cognition
impairment, neuropsychiatric and movement disorders. H2S has
been considered by US government as a high priority chemical
threat, both industrially and as a potential weapon of mass
destruction by terrorists. Currently, there is no antidote for H2S
poisoning and treatment is largely supportive. A cyanide
antidote-HC has been tested as H2S antidote.[9b, 16] It has shown
some benefit in animal models but has to be administered either
before or immediately after H2S exposure. Clinical use of HC for
H2S poisoning is still unsuccessful.[17] Obviously identification of
novel H2S antidotes is a national priority. We believe potent H2S
scavengers can be potential antidotes. Therefore, a scavenger
(SS20) was tested. Briefly, Na2S (125 mg/kg) was dissolved in
saline immediately before intraperitoneal (IP) injection to mice.
SS20, HC or vehicle (0.5% DMSO in saline) was administered
IP at 1 min after Na2S injection. While 4 out of 7 vehicle-treated
mice died (determined by a humane endpoint), all mice treated
with SS20 or HC survived after Na2S injection (Fig. 7). These
results suggest that sulfonyl azide-based scavengers effectively
scavenged H2S in vivo and may represent a new class of
effective antidote for H2S poisoning.
Acknowledgements
This work was supported by NIH DA046386 and NSF 1738305 to
M.X.; NSF 1557879 to F.I.
Keywords: H2S • scavenger • sensor • chemical probe
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Fig. 7 %Survival of mice intoxicated with H2S treated with SS20/HC/vehicle.
*P<0.05 vs vehicle
It should be noted that in this work we mainly focused on
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sulfur species such as H2Sn and persulfides. It is known that
H2S-producing enzymes (CBS, CSE, 3MST and CARS) also
produce H2Sn and persulfides and they are in equilibrium in
biological systems.[18] In actual cellular systems the presence of
free cysteine should facilitate interconversion of these species
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10.1002/anie.201905580
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COMMUNICATION
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10.1002/anie.201905580
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Chun-tao Yang, Yingying Wang, Eizo
Marutani, Tomoaki Ida, Xiang Ni, Shi
Xu, Wei Chen, Hui Zhang, Takaaki
Akaike, Fumito Ichinose, and Ming
Xian*
Data Inspired Discovery of H2S
Scavengers: Specific H2S scavengers are
critical research tools but have not been
identified. Inspired by the similar
chemistry/property between scavengers
and fluorescent sensors, we carried out
data-driven identification of H2S
Page No. – Page No.
Data-Driven Identification of
Hydrogen Sulfide Scavengers
scavengers. Sulfonyl azide based
molecules were found to be effective
scavengers which showed promising
activity in both in vitro and in vivo models.
This article is protected by copyright. All rights reserved.