Angewandte
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Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 6061–6067
Gasotransmitters
Hot Paper
Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome
Kearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone,
Veronica M. Ringel-Scaia, Ethan W. Winckler, R. McAlister Council-Troche, Irving C. Allen,*
À
Abstract: Persulfides (R SSH) have been hypothesized as
potent redox modulators and signaling compounds. Reported
herein is the synthesis, characterization, and in vivo evaluation
of a persulfide donor that releases N-acetyl cysteine persulfide
(NAC-SSH) in response to the prokaryote-specific enzyme
nitroreductase. The donor, termed NDP-NAC, decomposed in
response to E. coli nitroreductase, resulting in release of NAC-
SSH. NDP-NAC elicited gastroprotective effects in mice that
were not observed in animals treated with control compounds
incapable of persulfide release or in animals treated with Na2S.
NDP-NAC induced these effects by the upregulation of
beneficial small- and medium-chain fatty acids and through
increasing growth of Turicibacter sanguinis, a beneficial gut
bacterium. It also decreased the populations of Synergistales
bacteria, opportunistic pathogens implicated in gastrointestinal
infections. This study reveals the possibility of maintaining gut
health or treating microbiome-related diseases by the targeted
delivery of reactive sulfur species.
received considerable interest lately because of their role as
likely H2S signaling products, coupled with advances in redox
biology showing that native persulfides carry out specific,
antioxidative physiological functions.[11] Several persulfide-
releasing compounds (termed persulfide donors) release their
payload under a variety of conditions, including changes in
pH,[9d] and addition of fluoride,[12] hydrogen peroxide,[9b] or
esterases.[9a,c] These donors provide insight into persulfide
interactions from a systemic perspective, but it is difficult to
determine the role(s) persulfides may serve in specific areas
of the body due to a lack of persulfide donors with targeting
capabilities.
One particular area where persulfides may play important
physiological and/or pathophysiological roles is in the gut.[13]
The gut microbiome is a promising drug target because many
links have been discovered connecting microbiome health
and composition to a variety of human diseases. The effects of
exogenously delivered H2S in the microbiome are controver-
sial; some studies have shown beneficial effects of H2S in the
regeneration of colon epithelial tissues by decreasing local
inflammation,[14] while others have found harmful effects,
such as inhibiting colonocyte respiration and increasing
inflammation.[15] The discrepancies in the observed outcomes
of exogenously delivered H2S may be a result of inconsistent
delivery methods and concentrations, combined with the use
of H2S donors capable of reaching the bloodstream and
exerting off-target effects. As for other RSS, little is known;
for example, there exist no studies evaluating the effect of
persulfides in the microbiome due to a lack of persulfide
donors specifically activated in the gut.
We sought to address this lack of targeted persulfide
donors and gap in knowledge in how persulfide delivery
affects the gut microbiome by synthesizing a persulfide donor
that responds to the prokaryote enzyme nitroreductase (NR).
NRs are located specifically in bacteria, sequestered mostly in
the mouth, skin, and intestines in mammals. Pharmacologi-
cally, NRs have been utilized to trigger the release of a variety
of compounds ranging from prodrug systems[16] to chemical
probes used in imaging.[17] For example, Dubikovskaya
developed an NR-responsive caged luciferin probe for use
in gene-directed enzyme prodrug therapy. The probe fluor-
esced exclusively in the presence of NR, yielding a novel
method to view NR transformed cancer cells.[17a] Chakrapani
et al. reported the synthesis and characterization of an NR-
responsive nitric oxide (NO)-releasing prodrug.[16a] The donor
was stable in PBS buffer, but released NO selectively in
response to NR. Chakrapani also synthesized an NR-respon-
sive H2S prodrug by combining p-nitrobenzyl thiol with
a ketone to form a thioketal.[18] The donor released H2S in the
Introduction
Hydrogen sulfide (H2S) has been under investigation as
a biological signaling gas (gasotransmitter) since its physio-
logical signaling capacity was discovered in 1996.[1] To aid in
understanding its (patho)physiological roles, many different
types of donors have been synthesized with a variety of
triggers, including water,[2] nucleophiles,[3] light,[4] and en-
zymes.[5] Some may hold therapeutic value in the form of
prodrugs and drug conjugates.[6] More recently, additional
work has been conducted in the synthesis of compounds that
release a variety of related reactive sulfur species (RSS)
including carbonyl sulfide (COS),[7] sulfur dioxide (SO2),[8]
[9]
À
and persulfides (R SSH), with the goal of understanding
the specific roles of each of these RSS in the greater reactive
species interactome.[10] Of these RSS, persulfides have
[*] H. A. Morrison, V. M. Ringel-Scaia, R. M. Council-Troche, I. C. Allen
Department of Biomedical Sciences and Pathobiology
Virginia-Maryland College of Veterinary Medicine, Virginia Tech
Blacksburg, VA 24061 (USA)
E-mail: icallen@vt.edu
K. M. Dillon, C. R. Powell, R. J. Carrazzone, E. W. Winckler,
J. B. Matson
Department of Chemistry, Virginia Tech Center for Drug Discovery
and Macromolecules Innovation Institute, Virginia Tech
Blacksburg, VA 24061 (USA)
E-mail: jbmatson@vt.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2021, 60, 6061 –6067
ꢀ 2021 Wiley-VCH GmbH
6061