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Article ; Online: Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1.

Shillingford, Jonathan M / Shayman, James A

American journal of physiology. Renal physiology

2023 Volume 324, Issue 4, Page(s) F404–F422

Abstract: Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. Nuclear translocation and ... ...

Abstract	Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. Nuclear translocation and functional responses to TFEB activation were studied in three murine models of renal cystic disease, including knockouts of
MeSH term(s)	Animals ; Dogs ; Humans ; Mice ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Cysts ; Fibroblasts/metabolism ; Madin Darby Canine Kidney Cells ; Polycystic Kidney Diseases/metabolism ; Polycystic Kidney, Autosomal Dominant/metabolism ; TRPP Cation Channels/genetics
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; TFEB protein, human ; TRPP Cation Channels ; Tcfeb protein, mouse ; polycystic kidney disease 1 protein
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00237.2022
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Article ; Online: Post-infectious inflammatory syndrome associated with SARS-CoV-2 in a paediatric patient with Down syndrome.

Khoshnood, Mellad / Mahabir, Roshan / Shillingford, Nick M / Santoro, Jonathan D

BMJ case reports

2021 Volume 14, Issue 4

Abstract: Neurological complications of SARS-CoV-2 continue to be recognised. In children, neurological phenomenon has been reported generally in the acute infectious period. It is possible that SARS-CoV-2 could trigger an immune-mediated post-infectious ... ...

Abstract	Neurological complications of SARS-CoV-2 continue to be recognised. In children, neurological phenomenon has been reported generally in the acute infectious period. It is possible that SARS-CoV-2 could trigger an immune-mediated post-infectious phenomenon. Here, we present a unique case of post-infectious marantic cardiac lesion causing cerebrovascular accident in a patient with Down syndrome.
MeSH term(s)	COVID-19/complications ; Child ; Down Syndrome/complications ; Down Syndrome/virology ; Humans ; Inflammation/complications ; Inflammation/virology ; Nervous System Diseases/virology ; Stroke/virology
Language	English
Publishing date	2021-04-15
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2020-240490
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Article ; Online: Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis.

Hinkovska-Galcheva, Vania / Treadwell, Taylour / Shillingford, Jonathan M / Lee, Angela / Abe, Akira / Tesmer, John J G / Shayman, James A

Journal of lipid research

2021 Volume 62, Page(s) 100089

Abstract: Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of ... ...

Abstract	Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome-specific phospholipase A2 (PLA2G15) and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC
MeSH term(s)	Animals ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Lysosomes/enzymology ; Phospholipases A2/genetics ; Phospholipases A2/metabolism ; Phospholipids/metabolism
Chemical Substances	Enzyme Inhibitors ; Phospholipids ; Phospholipases A2 (EC 3.1.1.4)
Language	English
Publishing date	2021-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2021.100089
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Article ; Online: Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.

Gannam, Zira T K / Jamali, Haya / Kweon, Oh Sang / Herrington, James / Shillingford, Shanelle R / Papini, Christina / Gentzel, Erik / Lolis, Elias / Bennett, Anton M / Ellman, Jonathan A / Anderson, Karen S

European journal of medicinal chemistry

2022 Volume 243, Page(s) 114712

Abstract: Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease ... ...

Abstract	Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP5) is responsible for regulating the activity of the stress-responsive MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease a fatal rare disease which has neither a treatment nor cure. In previous work, we identified Compound 1 (3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one) as the lead compound of a novel class of MKP5 inhibitors. In this work, we explore the structure-activity relationship for inhibition of MKP5 through modifications to the scaffold and functional groups present in 1. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, the X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. We found that the parallel-displaced π-π interaction between the inhibitor three-ring core and Tyr435 is critical for modulating potency, and that modifications to the core and functionalization at the C-9 position are essential for ensuring proper positioning of the core for this interaction. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease.
MeSH term(s)	Structure-Activity Relationship
Language	English
Publishing date	2022-09-02
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2022.114712
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Article ; Online: Restoring and attributing ancient texts using deep neural networks.

Assael, Yannis / Sommerschield, Thea / Shillingford, Brendan / Bordbar, Mahyar / Pavlopoulos, John / Chatzipanagiotou, Marita / Androutsopoulos, Ion / Prag, Jonathan / de Freitas, Nando

Nature

2022 Volume 603, Issue 7900, Page(s) 280–283

Abstract: Ancient history relies on disciplines such as epigraphy-the study of inscribed texts known as inscriptions-for evidence of the thought, language, society and history of past ... ...

Abstract	Ancient history relies on disciplines such as epigraphy-the study of inscribed texts known as inscriptions-for evidence of the thought, language, society and history of past civilizations
MeSH term(s)	Archaeology/methods ; Deep Learning ; Greece, Ancient/ethnology ; Handwriting ; History, Ancient ; Humans ; Software ; Writing/history
Language	English
Publishing date	2022-03-09
Publishing country	England
Document type	Historical Article ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-022-04448-z
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Article: Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Weimbs, Thomas / Shillingford, Jonathan M / Torres, Jacob / Kruger, Samantha L / Bourgeois, Bryan C

Clinical kidney journal

2018 Volume 11, Issue Suppl 1, Page(s) i27–i38

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 ... ...

Abstract	Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art)
Language	English
Publishing date	2018-12-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2655800-2
ISSN	2048-8513 ; 2048-8505
ISSN (online)	2048-8513
ISSN	2048-8505
DOI	10.1093/ckj/sfy089
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Article ; Online: Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease.

Kipp, Kevin R / Kruger, Samantha L / Schimmel, Margaret F / Parker, Nikki / Shillingford, Jonathan M / Leamon, Christopher P / Weimbs, Thomas

American journal of physiology. Renal physiology

2018 Volume 315, Issue 2, Page(s) F395–F405

Abstract: Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, ...

Abstract	Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC-rapa are similarly effective on polycystic kidneys in this model. However, FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD.
MeSH term(s)	A549 Cells ; Animals ; Disease Models, Animal ; Drug Compounding ; Folate Receptor 1/metabolism ; Folic Acid/analogs & derivatives ; Folic Acid/metabolism ; Folic Acid/pharmacology ; Humans ; Integrases/genetics ; Kidney/drug effects ; Kidney/enzymology ; Mice, Knockout ; Polycystic Kidney, Autosomal Dominant/enzymology ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/prevention & control ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; TRPP Cation Channels/deficiency ; TRPP Cation Channels/genetics ; Tissue Distribution
Chemical Substances	Folate Receptor 1 ; Folr1 protein, mouse ; Protein Kinase Inhibitors ; TRPP Cation Channels ; polycystic kidney disease 1 protein ; Folic Acid (935E97BOY8) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2018-05-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00057.2018
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Article ; Online: Detecting Functional and Accessible Folate Receptor Expression in Cancer and Polycystic Kidneys.

Chu, Haiyan / Shillingford, Jonathan M / Reddy, Joseph A / Westrick, Elaine / Nelson, Melissa / Wang, Emilia Z / Parker, Nikki / Felten, Albert E / Vaughn, Jeremy F / Xu, Le-Cun / Lu, Yingjuan J / Vlahov, Iontcho R / Leamon, Christopher P

Molecular pharmaceutics

2019 Volume 16, Issue 9, Page(s) 3985–3995

Abstract: Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) ...

Abstract	Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection. Data show that EC2220 produces a far greater IHC signal in FRα-positive tissues over that produced with EC17, a folate-fluorescein SMRC that is released from the formaldehyde-denatured FRα protein. Furthermore, the extent of the EC2220 IHC signal was proportional to the level of FRα expression. This EC2220-based assay was qualified both
MeSH term(s)	A549 Cells ; Animals ; Doxycycline/pharmacology ; Fluorescein-5-isothiocyanate/chemistry ; Fluorescein-5-isothiocyanate/metabolism ; Folate Receptor 1/analysis ; Folate Receptor 1/metabolism ; Folic Acid/analogs & derivatives ; Folic Acid/chemistry ; Folic Acid/metabolism ; HeLa Cells ; Humans ; Lysine/analogs & derivatives ; Lysine/chemistry ; Lysine/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mice, Transgenic ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Oligopeptides/chemistry ; Oligopeptides/metabolism ; Polycystic Kidney Diseases/chemically induced ; Polycystic Kidney Diseases/drug therapy ; Polycystic Kidney Diseases/metabolism ; Protein Kinase C/genetics ; Tissue Distribution ; Trityl Compounds/chemistry ; Trityl Compounds/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	FOLR1 protein, human ; Folate Receptor 1 ; N(alpha)-9-fluorenylmethoxycarbonyl-N(epsilon)-4-methyltrityllysine ; Oligopeptides ; Trityl Compounds ; Folic Acid (935E97BOY8) ; protein kinase D (EC 2.7.10.-) ; Protein Kinase C (EC 2.7.11.13) ; Fluorescein-5-isothiocyanate (I223NX31W9) ; Lysine (K3Z4F929H6) ; Doxycycline (N12000U13O)
Language	English
Publishing date	2019-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.9b00624
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Article ; Online: Folate-conjugated rapamycin slows progression of polycystic kidney disease.

Shillingford, Jonathan M / Leamon, Christopher P / Vlahov, Iontcho R / Weimbs, Thomas

Journal of the American Society of Nephrology : JASN

2012 Volume 23, Issue 10, Page(s) 1674–1681

Abstract: Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown ... ...

Abstract	Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.
MeSH term(s)	Animals ; Cell Line ; Disease Models, Animal ; Endocytosis ; Folate Receptors, GPI-Anchored/metabolism ; Folic Acid/analogs & derivatives ; Folic Acid/therapeutic use ; Humans ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Mice ; Polycystic Kidney, Autosomal Dominant/drug therapy ; Polycystic Kidney, Autosomal Dominant/metabolism ; Polycystic Kidney, Autosomal Dominant/pathology ; Signal Transduction/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Folate Receptors, GPI-Anchored ; Folic Acid (935E97BOY8) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2012-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2012040367
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Article ; Online: An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.

Gannam, Zira T K / Min, Kisuk / Shillingford, Shanelle R / Zhang, Lei / Herrington, James / Abriola, Laura / Gareiss, Peter C / Pantouris, Georgios / Tzouvelekis, Argyrios / Kaminski, Naftali / Zhang, Xinbo / Yu, Jun / Jamali, Haya / Ellman, Jonathan A / Lolis, Elias / Anderson, Karen S / Bennett, Anton M

Science signaling

2020 Volume 13, Issue 646

Abstract: The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of ...

Abstract	The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38α MAPK-derived, phosphopeptide-based small-molecule screen. We solved the structure of MKP5 in complex with this inhibitor, which revealed a previously undescribed allosteric binding pocket. Binding of the inhibitor to this pocket collapsed the MKP5 active site and was predicted to limit MAPK binding. Treatment with the inhibitor recapitulated the phenotype of MKP5 deficiency, resulting in activation of p38 MAPK and JNK. We demonstrated that MKP5 was required for TGF-β1 signaling in muscle and that the inhibitor blocked TGF-β1-mediated Smad2 phosphorylation. TGF-β1 pathway antagonism has been proposed for the treatment of dystrophic muscle disease. Thus, allosteric inhibition of MKP5 represents a therapeutic strategy against dystrophic muscle disease.
MeSH term(s)	Allosteric Site/genetics ; Amino Acid Sequence ; Animals ; Cell Differentiation/drug effects ; Cell Line ; Dual-Specificity Phosphatases/antagonists & inhibitors ; Dual-Specificity Phosphatases/chemistry ; Dual-Specificity Phosphatases/metabolism ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Female ; High-Throughput Screening Assays/methods ; Humans ; Kinetics ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase Phosphatases/antagonists & inhibitors ; Mitogen-Activated Protein Kinase Phosphatases/chemistry ; Mitogen-Activated Protein Kinase Phosphatases/metabolism ; Myoblasts/cytology ; Myoblasts/drug effects ; Myoblasts/metabolism ; Protein Binding/drug effects ; Sequence Homology, Amino Acid ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology
Chemical Substances	Enzyme Inhibitors ; Small Molecule Libraries ; DUSP10 protein, human (EC 3.1.3.16) ; Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16) ; Dual-Specificity Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aba3043
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