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Article: Targeting the Ubiquinol-Reduction (Q

Amporndanai, Kangsa / Pinthong, Nattapon / O'Neill, Paul M / Hong, W David / Amewu, Richard K / Pidathala, Chandrakala / Berry, Neil G / Leung, Suet C / Ward, Stephen A / Biagini, Giancarlo A / Hasnain, S Samar / Antonyuk, Svetlana V

Biology

2022 Volume 11, Issue 8

Abstract: Antimalarials targeting the ubiquinol-oxidation ( ... ...

Abstract	Antimalarials targeting the ubiquinol-oxidation (Q
Language	English
Publishing date	2022-07-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology11081109
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.

Teuscher, Kevin B / Mills, Jonathan J / Tian, Jianhua / Han, Changho / Meyers, Kenneth M / Sai, Jiqing / South, Taylor M / Crow, Mackenzie M / Van Meveren, Mayme / Sensintaffar, John L / Zhao, Bin / Amporndanai, Kangsa / Moore, William J / Stott, Gordon M / Tansey, William P / Lee, Taekyu / Fesik, Stephen W

Journal of medicinal chemistry

2023 Volume 66, Issue 24, Page(s) 16783–16806

Abstract: The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against ... ...

Abstract	The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[
MeSH term(s)	Animals ; WD40 Repeats ; Drug Discovery ; Antineoplastic Agents/pharmacology
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01529
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Article ; Online: Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.

Amporndanai, Kangsa / Rogers, Michael / Watanabe, Seiji / Yamanaka, Koji / O'Neill, Paul M / Hasnain, S Samar

EBioMedicine

2020 Volume 59, Page(s) 102980

Abstract: Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS ... ...

Abstract	Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. Methods: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. Finding: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. Interpretation: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). Funding: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research (19KK0214) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
MeSH term(s)	Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/mortality ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Azoles/chemistry ; Azoles/metabolism ; Azoles/therapeutic use ; Betacoronavirus/metabolism ; Binding Sites ; Cell Line, Tumor ; Crystallography, X-Ray ; Dimerization ; Disease Models, Animal ; Enzyme Stability ; Mice ; Mice, Transgenic ; Molecular Dynamics Simulation ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/metabolism ; Neuroprotective Agents/therapeutic use ; Organoselenium Compounds/chemistry ; Organoselenium Compounds/metabolism ; Organoselenium Compounds/therapeutic use ; Protein Structure, Tertiary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; SARS-CoV-2 ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism ; Survival Rate ; Viral Matrix Proteins/chemistry ; Viral Matrix Proteins/metabolism
Chemical Substances	Azoles ; Neuroprotective Agents ; Organoselenium Compounds ; Recombinant Proteins ; Viral Matrix Proteins ; membrane protein, SARS-CoV-2 ; ebselen (40X2P7DPGH) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Keywords	covid19
Language	English
Publishing date	2020-08-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2020.102980
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Article: Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials

Amporndanai, Kangsa / Pinthong, Nattapon / O’Neill, Paul M. / Hong, W. David / Amewu, Richard K. / Pidathala, Chandrakala / Berry, Neil G. / Leung, Suet C. / Ward, Stephen A. / Biagini, Giancarlo A. / Hasnain, S. Samar / Antonyuk, Svetlana V.

Biology. 2022 July 25, v. 11, no. 8

2022

Abstract: Antimalarials targeting the ubiquinol-oxidation (Qₒ) site of the Plasmodium falciparum bc₁ complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qₒ site. Recent findings showed a ...

Abstract	Antimalarials targeting the ubiquinol-oxidation (Qₒ) site of the Plasmodium falciparum bc₁ complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qₒ site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc₁ complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc₁. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qᵢ sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc₁ with improved antimalarial properties.
Keywords	Plasmodium falciparum ; antimalarials ; cattle ; computer simulation ; drug resistance ; humans ; mitochondria ; models ; parasites ; quinolones ; ubiquinol-cytochrome-c reductase
Language	English
Dates of publication	2022-0725
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology11081109
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Purification and Structural Characterization of Aggregation-Prone Human TDP-43 Involved in Neurodegenerative Diseases.

Wright, Gareth S A / Watanabe, Tatiana F / Amporndanai, Kangsa / Plotkin, Steven S / Cashman, Neil R / Antonyuk, Svetlana V / Hasnain, S Samar

iScience

2020 Volume 23, Issue 6, Page(s) 101159

Abstract: Mislocalization, cleavage, and aggregation of the human protein TDP-43 is found in many neurodegenerative diseases. As is the case with many other proteins that are completely or partially structurally disordered, production of full-length recombinant ... ...

Abstract	Mislocalization, cleavage, and aggregation of the human protein TDP-43 is found in many neurodegenerative diseases. As is the case with many other proteins that are completely or partially structurally disordered, production of full-length recombinant TDP-43 in the quantities necessary for structural characterization has proved difficult. We show that the full-length TDP-43 protein and two truncated N-terminal constructs 1-270 and 1-263 can be heterologously expressed in E. coli. Full-length TDP-43 could be prevented from aggregation during purification using a detergent. Crystals grown from an N-terminal construct (1-270) revealed only the N-terminal domain (residues 1-80) with molecules arranged as parallel spirals with neighboring molecules arranged in head-to-tail fashion. To obtain detergent-free, full-length TDP-43 we mutated all six tryptophan residues to alanine. This provided sufficient soluble protein to collect small-angle X-ray scattering data. Refining relative positions of individual domains and intrinsically disordered regions against this data yielded a model of full-length TDP-43.
Language	English
Publishing date	2020-05-15
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101159
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

Amporndanai, Kangsa / Meng, Xiaoli / Shang, Weijuan / Jin, Zhenmig / Rogers, Michael / Zhao, Yao / Rao, Zihe / Liu, Zhi-Jie / Yang, Haitao / Zhang, Leike / O'Neill, Paul M / Samar Hasnain, S

Nature communications

2021 Volume 12, Issue 1, Page(s) 3061

Abstract: The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 ( ... ...

Abstract	The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M
MeSH term(s)	Antiviral Agents/pharmacology ; Azoles/chemistry ; Azoles/pharmacology ; Catalytic Domain ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/metabolism ; Crystallography, X-Ray ; Cysteine/chemistry ; Hydrolysis ; Models, Molecular ; Organoselenium Compounds/chemistry ; Organoselenium Compounds/pharmacology ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Reference Standards ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Salicylanilides/chemistry ; Salicylanilides/pharmacology ; Selenium/metabolism
Chemical Substances	Antiviral Agents ; Azoles ; Organoselenium Compounds ; Protease Inhibitors ; Salicylanilides ; ebselen (40X2P7DPGH) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; Selenium (H6241UJ22B) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2021-05-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-23313-7
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Article ; Online: Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Kangsa Amporndanai / Xiaoli Meng / Weijuan Shang / Zhenmig Jin / Michael Rogers / Yao Zhao / Zihe Rao / Zhi-Jie Liu / Haitao Yang / Leike Zhang / Paul M. O’Neill / S. Samar Hasnain

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 7

Abstract: Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, ... ...

Abstract	Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.
Keywords	Science ; Q
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel Selenium-based compounds with therapeutic potential for SOD1-linked amyotrophic lateral sclerosis

Kangsa Amporndanai / Michael Rogers / Seiji Watanabe / Koji Yamanaka / Paul M. O'Neill / S. Samar Hasnain

EBioMedicine, Vol 59, Iss , Pp 102980- (2020)

2020

Abstract	Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease as well as Lou Gehrig's disease, is a progressive neurological disorder selectively affecting motor neurons with no currently known cure. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene encoding superoxide dismutase1 (SOD1) enzyme. Aggregation of mutant SOD1 in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits. Methods: We have utilised the ebselen template to develop novel compounds that redeem stability of mutant SOD1 dimer and prevent aggregation. Binding modes of compounds have been visualised by crystallography. In vitro neuroprotection and toxicity of lead compounds have been performed in mouse neuronal cells and disease onset delay of ebselen has been demonstrated in transgenic ALS mice model. Finding: We have developed a number of ebselen-based compounds with improvements in A4V SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1. We also show clear disease onset delay of ebselen in transgenic ALS mice model holding encouraging promise for potential therapeutic compounds. Interpretation: Our finding established the new generation of organo-selenium compounds with better in vitro neuroprotective activity than edaravone. The potential of this class of compounds may offer an alternative therapeutic agent for ALS treatment. The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including main protease of SARS-Cov-2 (COVID-19). Funding: Project funding was supported by the ALS Association grant (WA1128) and Fostering Joint International Research ...
Keywords	SOD1 ; Ebselen ; Drug design ; Neurodegeneration ; Motor neuron disease ; COVID-19 ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	500
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: X-ray and cryo-EM structures of inhibitor-bound cytochrome

Amporndanai, Kangsa / Johnson, Rachel M / O'Neill, Paul M / Fishwick, Colin W G / Jamson, Alexander H / Rawson, Shaun / Muench, Stephen P / Hasnain, S Samar / Antonyuk, Svetlana V

IUCrJ

2018 Volume 5, Issue Pt 2, Page(s) 200–210

Abstract: ... ...

Abstract	Cytochrome
Language	English
Publishing date	2018-02-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2754953-7
ISSN	2052-2525
ISSN	2052-2525
DOI	10.1107/S2052252518001616
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Article ; Online: Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy.

Chantadul, Varunya / Wright, Gareth S A / Amporndanai, Kangsa / Shahid, Munazza / Antonyuk, Svetlana V / Washbourn, Gina / Rogers, Michael / Roberts, Natalie / Pye, Matthew / O'Neill, Paul M / Hasnain, S Samar

Communications biology

2020 Volume 3, Issue 1, Page(s) 97

Abstract: Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations ... ...

Abstract	Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.
MeSH term(s)	Amino Acid Substitution/genetics ; Azoles/chemical synthesis ; Azoles/chemistry ; Azoles/pharmacology ; Azoles/therapeutic use ; Crystallography, X-Ray ; Drug Design ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Isoindoles ; Models, Molecular ; Molecular Chaperones/chemical synthesis ; Molecular Chaperones/chemistry ; Molecular Chaperones/therapeutic use ; Molecular Docking Simulation ; Motor Neuron Disease/drug therapy ; Motor Neuron Disease/genetics ; Motor Neuron Disease/metabolism ; Motor Neuron Disease/pathology ; Mutant Proteins/chemistry ; Mutant Proteins/drug effects ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Mutation, Missense ; Organoselenium Compounds/chemical synthesis ; Organoselenium Compounds/chemistry ; Organoselenium Compounds/isolation & purification ; Organoselenium Compounds/pharmacology ; Organoselenium Compounds/therapeutic use ; Protein Folding/drug effects ; Protein Multimerization/drug effects ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Sulfur Compounds/chemical synthesis ; Sulfur Compounds/chemistry ; Superoxide Dismutase-1/chemistry ; Superoxide Dismutase-1/drug effects ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism ; Thermodynamics
Chemical Substances	Azoles ; Isoindoles ; Molecular Chaperones ; Mutant Proteins ; Organoselenium Compounds ; SOD1 protein, human ; Sulfur Compounds ; ebsulfur ; ebselen (40X2P7DPGH) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2020-03-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-020-0826-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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