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Article ; Online: Auranofin Resistance in

Ma, Christopher I / Tirtorahardjo, James A / Jan, Sharon / Schweizer, Sakura S / Rosario, Shawn A C / Du, Yanmiao / Zhang, Jerry J / Morrissette, Naomi S / Andrade, Rosa M

Frontiers in cellular and infection microbiology

2021 Volume 11, Page(s) 618994

Abstract: Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, ... ...

Abstract	Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including
MeSH term(s)	Animals ; Auranofin/pharmacology ; Parasites ; Reactive Oxygen Species ; Thioredoxin-Disulfide Reductase/genetics ; Toxoplasma/genetics
Chemical Substances	Reactive Oxygen Species ; Auranofin (3H04W2810V) ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9)
Language	English
Publishing date	2021-03-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2021.618994
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Synthetic Chondramide A Analogues Stabilize Filamentous Actin and Block Invasion by Toxoplasma gondii

Ma, Christopher I / Diraviyam Karthikeyan / Maier Martin E / Sept David / Sibley L. David

Journal of natural products. 2013 Sept. 27, v. 76, no. 9

2013

Abstract: Apicomplexan parasites such as Toxoplasma gondii rely on actin-based motility to cross biological barriers and invade host cells. Key structural and biochemical differences in host and parasite actins make this an attractive target for small-molecule ... ...

Abstract	Apicomplexan parasites such as Toxoplasma gondii rely on actin-based motility to cross biological barriers and invade host cells. Key structural and biochemical differences in host and parasite actins make this an attractive target for small-molecule inhibitors. Here we took advantage of recent advances in the synthesis of cyclic depsipeptide compounds that stabilize filamentous actin to test the ability of chondramides to disrupt growth of T. gondii in vitro. Structural modeling of chondramide A (2) binding to an actin filament model revealed variations in the binding site between host and parasite actins. A series of 10 previously synthesized analogues (2bâk) with substitutions in the Î²-tyrosine moiety blocked parasite growth on host cell monolayers with ECââ values that ranged from 0.3 to 1.3 Î¼M. In vitro polymerization assays using highly purified recombinant actin from T. gondii verified that synthetic and natural product chondramides target the actin cytoskeleton. Consistent with this, chondramide treatment blocked parasite invasion into host cells and was more rapidly effective than pyrimethamine, a standard therapeutic agent. Although the current compounds lack specificity for parasite vs host actin, these studies provide a platform for the future design and synthesis of synthetic cyclic peptide inhibitors that selectively disrupt actin dynamics in parasites.
Keywords	Toxoplasma gondii ; actin ; binding sites ; median effective concentration ; microfilaments ; models ; parasites ; polymerization ; pyrimethamine
Language	English
Dates of publication	2013-0927
Size	p. 1565-1572.
Publishing place	American Chemical Society and American Society of Pharmacognosy
Document type	Article
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021%2Fnp400196w
Database	NAL-Catalogue (AGRICOLA)

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Article: Toxoplasma gondii Profilin Acts Primarily To Sequester G-Actin While Formins Efficiently Nucleate Actin Filament Formation in Vitro

Skillman, Kristen M / Daher Wassim / Ma Christopher I / Soldati-Favre Dominique / Sibley L. David

Biochemistry. 2012 Mar. 27, v. 51, no. 12

2012

Abstract: Apicomplexan parasites employ gliding motility that depends on the polymerization of parasite actin filaments for host cell entry. Despite this requirement, parasite actin remains almost entirely unpolymerized at steady state; formation of filaments ... ...

Abstract	Apicomplexan parasites employ gliding motility that depends on the polymerization of parasite actin filaments for host cell entry. Despite this requirement, parasite actin remains almost entirely unpolymerized at steady state; formation of filaments required for motility relies on a small repertoire of actin-binding proteins. Previous studies have shown that apicomplexan formins and profilin exhibit canonical functions on heterologous actins from higher eukaryotes; however, their biochemical properties on parasite actins are unknown. We therefore analyzed the impact of T. gondii profilin (TgPRF) and FH1-FH2 domains of two formin isoforms in T. gondii (TgFRM1 and TgFRM2) on the polymerization of T. gondii actin (TgACTI). Our findings based on in vitro assays demonstrate that TgFRM1-FH1-FH2 and TgFRM2-FH1-FH2 dramatically enhanced TgACTI polymerization in the absence of profilin, making them the sole protein factors known to initiate polymerization of this normally unstable actin. In addition, T. gondii formin domains were shown to both initiate polymerization and induce bundling of TgACTI filaments; however, they did not rely on TgPRF for these activities. In contrast, TgPRF sequestered TgACTI monomers, thus inhibiting polymerization even in the presence of formins. Collectively, these findings provide insight into the unusual control mechanisms of actin dynamics within the parasite.
Keywords	Toxoplasma gondii ; actin ; eukaryotic cells ; in vitro studies ; microfilaments ; parasites ; polymerization
Language	English
Dates of publication	2012-0327
Size	p. 2486-2495.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi201704y
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Article ; Online: Synthetic chondramide A analogues stabilize filamentous actin and block invasion by Toxoplasma gondii.

Ma, Christopher I / Diraviyam, Karthikeyan / Maier, Martin E / Sept, David / Sibley, L David

Journal of natural products

2013 Volume 76, Issue 9, Page(s) 1565–1572

Abstract	Apicomplexan parasites such as Toxoplasma gondii rely on actin-based motility to cross biological barriers and invade host cells. Key structural and biochemical differences in host and parasite actins make this an attractive target for small-molecule inhibitors. Here we took advantage of recent advances in the synthesis of cyclic depsipeptide compounds that stabilize filamentous actin to test the ability of chondramides to disrupt growth of T. gondii in vitro. Structural modeling of chondramide A (2) binding to an actin filament model revealed variations in the binding site between host and parasite actins. A series of 10 previously synthesized analogues (2b-k) with substitutions in the β-tyrosine moiety blocked parasite growth on host cell monolayers with EC₅₀ values that ranged from 0.3 to 1.3 μM. In vitro polymerization assays using highly purified recombinant actin from T. gondii verified that synthetic and natural product chondramides target the actin cytoskeleton. Consistent with this, chondramide treatment blocked parasite invasion into host cells and was more rapidly effective than pyrimethamine, a standard therapeutic agent. Although the current compounds lack specificity for parasite vs host actin, these studies provide a platform for the future design and synthesis of synthetic cyclic peptide inhibitors that selectively disrupt actin dynamics in parasites.
MeSH term(s)	Actin Cytoskeleton/drug effects ; Actin Cytoskeleton/physiology ; Animals ; Binding Sites ; Depsipeptides/chemical synthesis ; Depsipeptides/chemistry ; Depsipeptides/pharmacology ; Microfilament Proteins/drug effects ; Microfilament Proteins/metabolism ; Protozoan Proteins/metabolism ; Toxoplasma/drug effects ; Toxoplasma/metabolism
Chemical Substances	Depsipeptides ; Microfilament Proteins ; Protozoan Proteins ; chondramide A
Language	English
Publishing date	2013-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/np400196w
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Article ; Online: Toxoplasma gondii profilin acts primarily to sequester G-actin while formins efficiently nucleate actin filament formation in vitro.

Skillman, Kristen M / Daher, Wassim / Ma, Christopher I / Soldati-Favre, Dominique / Sibley, L David

Biochemistry

2012 Volume 51, Issue 12, Page(s) 2486–2495

Abstract	Apicomplexan parasites employ gliding motility that depends on the polymerization of parasite actin filaments for host cell entry. Despite this requirement, parasite actin remains almost entirely unpolymerized at steady state; formation of filaments required for motility relies on a small repertoire of actin-binding proteins. Previous studies have shown that apicomplexan formins and profilin exhibit canonical functions on heterologous actins from higher eukaryotes; however, their biochemical properties on parasite actins are unknown. We therefore analyzed the impact of T. gondii profilin (TgPRF) and FH1-FH2 domains of two formin isoforms in T. gondii (TgFRM1 and TgFRM2) on the polymerization of T. gondii actin (TgACTI). Our findings based on in vitro assays demonstrate that TgFRM1-FH1-FH2 and TgFRM2-FH1-FH2 dramatically enhanced TgACTI polymerization in the absence of profilin, making them the sole protein factors known to initiate polymerization of this normally unstable actin. In addition, T. gondii formin domains were shown to both initiate polymerization and induce bundling of TgACTI filaments; however, they did not rely on TgPRF for these activities. In contrast, TgPRF sequestered TgACTI monomers, thus inhibiting polymerization even in the presence of formins. Collectively, these findings provide insight into the unusual control mechanisms of actin dynamics within the parasite.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/chemistry ; Actins/metabolism ; Nucleotides/metabolism ; Profilins/metabolism ; Protein Multimerization ; Protein Structure, Quaternary ; Protozoan Proteins/metabolism ; Toxoplasma/cytology ; Toxoplasma/metabolism
Chemical Substances	Actins ; Nucleotides ; Profilins ; Protozoan Proteins
Language	English
Publishing date	2012-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi201704y
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Article ; Online: The unusual dynamics of parasite actin result from isodesmic polymerization.

Skillman, Kristen M / Ma, Christopher I / Fremont, Daved H / Diraviyam, Karthikeyan / Cooper, John A / Sept, David / Sibley, L David

Nature communications

2013 Volume 4, Page(s) 2285

Abstract: Previous reports have indicated that parasite actins are short and inherently unstable, despite being required for motility. Here we re-examine the polymerization properties of actin in Toxoplasma gondii, unexpectedly finding that it exhibits isodesmic ... ...

Abstract	Previous reports have indicated that parasite actins are short and inherently unstable, despite being required for motility. Here we re-examine the polymerization properties of actin in Toxoplasma gondii, unexpectedly finding that it exhibits isodesmic polymerization in contrast to the conventional nucleation-elongation process of all previously studied actins from both eukaryotes and bacteria. Polymerization kinetics of actin in T. gondii lacks both a lag phase and critical concentration, normally characteristic of actins. Unique among actins, the kinetics of assembly can be fit with a single set of rate constants for all subunit interactions, without need for separate nucleation and elongation rates. This isodesmic model accurately predicts the assembly, disassembly and the size distribution of actin filaments in T. gondii in vitro, providing a mechanistic explanation for actin dynamics in vivo. Our findings expand the repertoire of mechanisms by which actin polymerization is governed and offer clues about the evolution of self-assembling, stabilized protein polymers.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/metabolism ; Animals ; Buffers ; Kinetics ; Light ; Models, Biological ; Parasites/metabolism ; Polymerization ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Scattering, Radiation ; Solutions ; Toxoplasma/metabolism
Chemical Substances	Actins ; Buffers ; Saccharomyces cerevisiae Proteins ; Solutions
Language	English
Publishing date	2013-07-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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/ncomms3285
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Article ; Online: Single-nucleus RNA-seq of differentiating human myoblasts reveals the extent of fate heterogeneity.

Zeng, Weihua / Jiang, Shan / Kong, Xiangduo / El-Ali, Nicole / Ball, Alexander R / Ma, Christopher I-Hsing / Hashimoto, Naohiro / Yokomori, Kyoko / Mortazavi, Ali

Nucleic acids research

2016 Volume 44, Issue 21, Page(s) e158

Abstract: Myoblasts are precursor skeletal muscle cells that differentiate into fused, multinucleated myotubes. Current single-cell microfluidic methods are not optimized for capturing very large, multinucleated cells such as myotubes. To circumvent the problem, ... ...

Abstract	Myoblasts are precursor skeletal muscle cells that differentiate into fused, multinucleated myotubes. Current single-cell microfluidic methods are not optimized for capturing very large, multinucleated cells such as myotubes. To circumvent the problem, we performed single-nucleus transcriptome analysis. Using immortalized human myoblasts, we performed RNA-seq analysis of single cells (scRNA-seq) and single nuclei (snRNA-seq) and found them comparable, with a distinct enrichment for long non-coding RNAs (lncRNAs) in snRNA-seq. We then compared snRNA-seq of myoblasts before and after differentiation. We observed the presence of mononucleated cells (MNCs) that remained unfused and analyzed separately from multi-nucleated myotubes. We found that while the transcriptome profiles of myoblast and myotube nuclei are relatively homogeneous, MNC nuclei exhibited significant heterogeneity, with the majority of them adopting a distinct mesenchymal state. Primary transcripts for microRNAs (miRNAs) that participate in skeletal muscle differentiation were among the most differentially expressed lncRNAs, which we validated using NanoString. Our study demonstrates that snRNA-seq provides reliable transcriptome quantification for cells that are otherwise not amenable to current single-cell platforms. Our results further indicate that snRNA-seq has unique advantage in capturing nucleus-enriched lncRNAs and miRNA precursors that are useful in mapping and monitoring differential miRNA expression during cellular differentiation.
MeSH term(s)	Cell Differentiation/genetics ; Cell Line ; Cell Nucleus/genetics ; Gene Expression Regulation ; Humans ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/physiology ; MicroRNAs/genetics ; Muscle Fibers, Skeletal/cytology ; Myoblasts/cytology ; Myoblasts/physiology ; Myogenic Regulatory Factor 5/genetics ; RNA, Long Noncoding ; Sequence Analysis, RNA/methods ; Single-Cell Analysis/methods
Chemical Substances	MIRN222 microRNA, human ; MYF5 protein, human ; MicroRNAs ; Myogenic Regulatory Factor 5 ; RNA, Long Noncoding
Language	English
Publishing date	2016-08-26
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkw739
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Article ; Online: Synthesis of chondramide A analogues with modified β-tyrosine and their biological evaluation.

Zhdanko, Alexander / Schmauder, Anke / Ma, Christopher I / Sibley, L David / Sept, David / Sasse, Florenz / Maier, Martin E

Chemistry (Weinheim an der Bergstrasse, Germany)

2011 Volume 17, Issue 47, Page(s) 13349–13357

Abstract: Starting from cinnamates 9, obtained by Wittig reaction or Heck coupling, the diols 17 were prepared by asymmetric dihydroxylation. This was followed by a regioselective substitution of the 3-OH group with hydrazoic acid under Mitsunobu conditions. ... ...

Abstract	Starting from cinnamates 9, obtained by Wittig reaction or Heck coupling, the diols 17 were prepared by asymmetric dihydroxylation. This was followed by a regioselective substitution of the 3-OH group with hydrazoic acid under Mitsunobu conditions. Methylation of the 2-OH group and reduction of the azide group led to the β-tyrosine derivatives 8. Condensation with the dipeptide acid 6 furnished the tripeptide part of the chondramides. The derived acids 21 were combined with the hydroxy ester 7 to the esters 22. Cleavage of the tert-butyl groups and intramolecular lactam formation gave rise to the chondramide A analogues 2 b-k. Growth inhibition assays showed most of the analogues to be biologically active. Some of them even reach the activity of jasplakinolide. It can be concluded that the 4-position of the aryl ring in the β-tyrosine of chondramide A tolerates structural modifications quite well.
MeSH term(s)	Bacterial Proteins/chemical synthesis ; Bacterial Proteins/chemistry ; Biological Factors/chemistry ; Depsipeptides/chemical synthesis ; Depsipeptides/chemistry ; Molecular Structure ; Oligopeptides/chemistry ; Stereoisomerism ; Tyrosine/chemistry
Chemical Substances	Bacterial Proteins ; Biological Factors ; Depsipeptides ; Oligopeptides ; chondramide A ; Tyrosine (42HK56048U)
Language	English
Publishing date	2011-10-20
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.201101978
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Article: Toxoplasma gondii Profilin Acts Primarily To Sequester G-Actin While Formins Efficiently Nucleate Actin Filament Formation in Vitro

Skillman, Kristen M. / Daher WassimauthorDepartment of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland / Ma Christopher I.authorDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States / Soldati-Favre DominiqueauthorDepartment of Microbiology and Molecular Medicine, CMU, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland / Sibley L. DavidauthorDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States

Language	English
Document type	Article
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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