10.1002/anie.201812668
Angewandte Chemie International Edition
COMMUNICATION
Identification and directed development of non-organic catalysts
with apparent pan-enzymatic mimicry into nanozymes for
efficient prodrug conversion
Raoul Walther,a # Anna K. Winther,a # Anne Sofie Fruergaard,a Wouter van den Akker,a Lise Sørensen,a
Signe Maria Nielsen,a,b Morten T. Jarlstad Olesen,a,b Yitao Dai,b Henrik S. Jeppesen,b Paolo Lamagni,b
Aleksandr Savateev,c Søren Lykke Pedersen,a Camilla Kaas Frich,a Cécile Vigier-Carrière,a Nina
Lock,a,b Mandeep Singh,d Vipul Bansal,d Rikke L. Meyer,b Alexander N. Zelikina,b
*
Abstract: Nanozymes, nanoparticles that mimic the natural activity of
enzymes, are intriguing academically and are important in the context
of Origin of Life. However, current nanozymes offer mimicry to a
narrow range of mammalian enzymes, near-exclusively performing
redox reactions. In this work, we present an unexpected discovery of
non-proteinaceous enzymes based on metals, metal oxides, 1D/2D-
materials, and non-metallic nanomaterials. Specific novelty of our
findings lies in the identification of nanozymes with apparent mimicry
of diverse mammalian enzymes, including unique pan-glycosidases.
Further novelty lies in the identification of the substrate scope for the
lead candidates, specifically in the context of bioconversion of
glucuronides, that is, human metabolites and privileged prodrugs in
the field of enzyme-prodrug therapies. Lastly, nanozymes are
employed for conversion of glucuronide prodrugs into marketed anti-
inflammatory and antibacterial agents, as well as “nanozyme prodrug
therapy” to mediate antibacterial measures.
dimension) is considered highly important in the context of Origin
[3]
of Life.
However, successful in their own right, current
nanozymes and mineral surfaces offer mimicry to a very narrow
range of mammalian enzymes, almost exclusively performing
redox reactions.[4] Compared to the magnitude of enzymes in the
human body, this range is only humble at the very best.
In this work, we present a highly unexpected identification of
nanozymes with apparent mimicry of diverse mammalian
enzymes performed under physiological conditions, including
non-proteinaceous pan-glycosidases. This was accomplished via
a screen of ca. 100 enzyme-mimic candidate materials against ca.
20 fluoro/chromogenic substrates. Specific novelty lies in that we
identified non-proteinaceous enzymes based on metals, metal
oxides, 1D/2D-materials, and non-metallic nanomaterials
(detailed in Supporting Information, Figures S10-S31). Further
novelty lies in that we identified the substrate scope for the lead
nanozymes, specifically in the context of bioconversion of
glucuronides, that is, natural metabolites and privileged prodrugs
in the field of enzyme-prodrug therapies.[5] Lead nanozymes
performed efficient conversion of glucuronide prodrugs to
produce anti-inflammatory and antibacterial agents. To our
knowledge, we report the first example of pan-enzymatic mimicry
evidenced in non-proteinaceous materials, as well as the first
example of nanozymes as mimics of glucuronidase for enzyme-
prodrug therapy.
Nanoparticles that mimic the natural activity of enzymes, termed
nanozymes, comprise a unique set of materials at the interface
[1]
between inorganic and bio-organic chemistry.
Engineering
mammalian enzyme-like behavior into non-proteinaceous
molecules is intriguing academically and is poised to open up
immense opportunities in biotechnology and biomedicine.
Specifically, advantages of nanozymes over the natural enzymes
include stability, scalability, chemical diversity, and performance
in non-aqueous solvents.[2] From
enzymatic activity of inorganic materials (regardless of their
a different perspective,
[6]
With our broader interest in enzyme prodrug therapies (EPT),
the first screen of nanomaterials for potential enzymatic activity
performed in this work aimed to identify mimics of glucuronidase.
Glucuronides hold a privileged position in EPT[5] and are also
natural metabolites that are formed during phase II metabolism in
the human liver. Enzyme activity was evaluated with the use of a
turn-on fluorescent probe, resorufin--D-glucuronide (Figure 1A).
Over a 24 h incubation time, inorganic enzyme-mimics afforded
conversion of the substrate to yield fluorescent product in content
as high as 1 µM (Figure 1B). The catalytic activity of the particles
was readily registered by fluorescence imaging which showed
significant increase in the fluorescence of substrate solutions in
the presence of nanozymes (Figure 1C). Strikingly, enzyme
mimics were identified within each class of nanomaterials tested
and leads included metals, metal oxides, 1D/2D materials and
non-metallic nanoparticles.
[a]
[b]
R. Walther, A.K. Winther, W. van den Akker, A.S. Fruergaard, L.
Sørensen, S.M. Nielsen, M.T. Jarlstad Olesen, S.L. Pedersen, C.K.
Frich, C. Vigier-Carrièr,
Department of Chemistry, Aarhus University, Aarhus, Denmark
E-mail: zelikin@chem.au.dk
Y. Dai, H.S. Jeppesen, P. Lamagni, Dr. N. Lock, Dr. R.L. Meyer, Dr.
A.N. Zelikin
iNano Interdisciplinary Nanoscience Centre, Aarhus University,
Aarhus, Denmark
Dr. Aleksandr Savateev
Max-Planck Institute of Colloids and Interfaces, Potsdam, Germany
M. Singh, Prof. Vipul Bansal
RMIT University, Melbourne, Australia
These authors contributed equally
[c]
[d]
#
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.