scholarly journals Mitochondria-Targeted Inhibitors of the Human SIRT3 Lysine Deacetylase

Author(s):  
Kathrin Sten Troelsen ◽  
Michael Bæk, ◽  
Alexander Lund Nielsen ◽  
Andreas Stahl Madasen ◽  
Nima Rajabi ◽  
...  

<p>Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in the mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as a potential drug target in certain cancers. Investigation of pharmacological intervention has been challenging due to a lack of potent and selective inhibitors of SIRT3. Here, we developed a strategy for selective inhibition of SIRT3 in cells, over its structurally similar isozymes that localize primarily to nucleus (SIRT1) and cytoplasm (SIRT2). This was achieved by directing the inhibitors straight to the mitochondria through incorporation of sequences inspired by previously described mitochondria-targeting peptides. Our inhibitors exhibited excellent mitochondrial localization in HeLa cells as indicated by fluorophore-conjugated versions and target engagement was demonstrated by a thermal shift assay of SIRT3 using western blotting. The acetylation state of documented SIRT3 target MnSOD was shown to be perturbed in cells with little effect on known targets of SIRT1 and SIRT2, showing that our lead compound exhibits selectivity for SIRT3 in cells. We expect that the developed inhibitor will now enable a more detailed investigation of SIRT3 as a potential drug target and help shed further light on the diverse biology regulated by this enzyme. </p>

2020 ◽  
Author(s):  
Kathrin Sten Troelsen ◽  
Michael Bæk, ◽  
Andreas Stahl Madasen ◽  
Nima Rajabi ◽  
Christian Adam Olsen

<p>Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in the mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as a potential drug target in certain cancers. Investigation of pharmacological intervention has been challenging due to a lack of potent and selective inhibitors of SIRT3. Here, we developed a strategy for selective inhibition of SIRT3 in cells, over its structurally similar isozymes that localize primarily to nucleus (SIRT1) and cytoplasm (SIRT2). This was achieved by directing the inhibitors straight to the mitochondria through incorporation of sequences inspired by previously described mitochondria-targeting peptides. Our inhibitors exhibited excellent mitochondrial localization in HeLa cells as indicated by fluorophore-conjugated versions and target engagement was demonstrated by a thermal shift assay of SIRT3 using western blotting. The acetylation state of documented SIRT3 target MnSOD was shown to be perturbed in cells with little effect on known targets of SIRT1 and SIRT2, showing that our lead compound exhibits selectivity for SIRT3 in cells. We expect that the developed inhibitor will now enable a more detailed investigation of SIRT3 as a potential drug target and help shed further light on the diverse biology regulated by this enzyme. </p>


2020 ◽  
Author(s):  
Kathrin Sten Troelsen ◽  
Michael Bæk, ◽  
Alexander Lund Nielsen ◽  
Andreas Stahl Madasen ◽  
Nima Rajabi ◽  
...  

<p>Sirtuin 3 (SIRT3) is the major protein lysine deacetylase in the mitochondria. This hydrolase regulates a wide range of metabolically involved enzymes and has been considered as a potential drug target in certain cancers. Investigation of pharmacological intervention has been challenging due to a lack of potent and selective inhibitors of SIRT3. Here, we developed a strategy for selective inhibition of SIRT3 in cells, over its structurally similar isozymes that localize primarily to nucleus (SIRT1) and cytoplasm (SIRT2). This was achieved by directing the inhibitors straight to the mitochondria through incorporation of sequences inspired by previously described mitochondria-targeting peptides. Our inhibitors exhibited excellent mitochondrial localization in HeLa cells as indicated by fluorophore-conjugated versions and target engagement was demonstrated by a thermal shift assay of SIRT3 using western blotting. The acetylation state of documented SIRT3 target MnSOD was shown to be perturbed in cells with little effect on known targets of SIRT1 and SIRT2, showing that our lead compound exhibits selectivity for SIRT3 in cells. We expect that the developed inhibitor will now enable a more detailed investigation of SIRT3 as a potential drug target and help shed further light on the diverse biology regulated by this enzyme. </p>


Parasitology ◽  
2013 ◽  
Vol 141 (1) ◽  
pp. 37-49 ◽  
Author(s):  
EDWARD W. TATE ◽  
ANDREW S. BELL ◽  
MARK D. RACKHAM ◽  
MEGAN H. WRIGHT

SUMMARYInfections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.


2013 ◽  
Vol 19 (14) ◽  
pp. 2637-2648 ◽  
Author(s):  
Ana Serrano ◽  
Patricia Ferreira ◽  
Marta Martinez-Julvez ◽  
Milagros Medina

2019 ◽  
Vol 20 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Lalit Kumar Gautam ◽  
Prince Sharma ◽  
Neena Capalash

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.


2011 ◽  
Vol 8 (4) ◽  
pp. 363-370 ◽  
Author(s):  
Lakshminarayanan Karthik ◽  
Palayam Malathy ◽  
Annie Trinitta ◽  
Krishnasamy Gunasekaran

2021 ◽  
Author(s):  
Nattawadee Panyain ◽  
Aurélien Godinat ◽  
Aditya Raymond Thawani ◽  
Sofía Lachiondo-Ortega ◽  
Katie Mason ◽  
...  

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1...


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