Introducing Our Authors pubs.acs.org/acschemicalbiology
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DENNIS BENSINGER
MICKAËL LELIMOUSIN
Image courtesy of Jan-Pascal Kahler.
Image courtesy of Bruno Jean.
Education: Technical University of Darmstadt, B.Sc. in Chemistry 2011; Ecole Nationale Supérieure de Chimie de Montpellier, France, and Technical University of Darmstadt, M.Sc. in Chemistry 2014 Current Position: Ph.D. student in the laboratory of Professor Boris Schmidt at the Technical University of Darmstadt, Department of Organic Chemistry and Biochemistry, Germany Nonscientific Interests: Volunteer firefighter, soccer, traveling, and BBQ My graduate research is focused on the development of kinase and protease inhibitors targeting hematological cancers. For the optimization of therapeutically useful small molecules, we develop and apply organic synthesis as well as computational and biochemical methods that lead us to improved inhibitors more efficiently. In our recent paper, we describe a series of S1-derived proteasome inhibitors and analogue substrates based on a uniquely β5-selective tripeptide aldehyde inhibitor that is in preclinical studies currently. We observe opposed behavior of substrate hydrolysis, which favors small residues, whereas inhibitor strength favors large residues. Michaelis−Menten analysis revealed that elastase-like activity is superior to the chymotrypsin-like activity. Selective chemical silencing proofed the superiority of small S1-residue containing substrates to the standard tyrosine-containing substrate. We hope that these findings will lead to more potent and subunit-selective proteasome inhibitors in future work. (Read Bensinger’s article DOI: 10.1021/acschembio.6b00023)
Education: University of Oxford, Assistant Researcher with Prof. Mark Sansom, 2010−2014; International School for Advanced Studies, Postdoctoral Fellow with Prof. Paolo Carloni, 2009−2010; Université Joseph Fourier, Ph.D. Physical Chemistry, 2009, and M.A. Structural Biology, 2005, with Prof. Martin Field Current Position: CNRS, Assistant Researcher in Prof. Anne Imberty’s Lab since January 2015 Nonscientific Interests: Sports, arts, mountains, and traveling My research aims to unveil some dynamic features of biological molecules by numerical simulations. Computational techniques give a fascinating opportunity to glean highresolution information that is often inaccessible through experiments. I enjoy developing and using some multiscale modeling approaches to investigate biological processes going from ultrafast quantum effects to large-scale motions of complex proteins. In the present study, we report the unusual distortion of the human histo-blood group antigen Lewis x by pathogen lectins. The complementarity of a series of experimental and computational results illustrates how useful simulations can be to identify and to characterize functionally relevant motions. Our findings also show that conformational dynamics is important in cell recognition and should be considered when designing glyco-derived compounds of therapeutical interest. (Read Lelimousin’s article DOI: 10.1021/acschembio.6b00333)
Published: July 15, 2016 © 2016 American Chemical Society
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DOI: 10.1021/acschembio.6b00577 ACS Chem. Biol. 2016, 11, 1765−1768
ACS Chemical Biology
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Introducing Our Authors
SAMSUZZOHA MONDAL
Current Position: Ph.D. student in the laboratory of Prof. Boris Schmidt at the Technical University of Darmstadt, Department of Organic Chemistry and Biochemistry, Germany Nonscientific Interests: Pilates, running, hiking, traveling, and cooking My Ph.D. research is focused on the design, synthesis, and evaluation of inhibitors for proteases and kinases related to cancer. For example, in one of my research projects, I could confirm the potential of GSK-3α inhibition in the therapy of acute myeloid leukemia. This paper is about targeting the β5 subunit of the proteasome for therapy of hematologic cancers. We have found that the standard tyrosine-containing substrate for investigation of novel inhibitors is cleaved unselectively. Consequently, selectivity and potency of new inhibitors against the β5 subunit are often determined inaccurately. Therefore, we recommend replacing the standard substrate with our investigated substrate. Hopefully, use of our substrate will aid in the design of promising therapeutic candidates in hematologic cancers. (Read Neumann’s article DOI: 10.1021/ acschembio.6b00023)
Image courtesy of Aromal Asokan.
Education: University of Burdwan, B.Sc. in Chemistry, 2009; Indian Institute of Technology, Kharagpur, M.Sc. in Chemistry, 2011 Current Position: Ph.D. candidate at Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, Advisor: Dr. Ankona Datta Nonscientific Interests: Music, travel, and movies My Ph.D. research is focused on the development of fluorescent probes for imaging phospholipids that mediate cell signaling. Tracking the spatiotemporal dynamics of phospholipids on cell membranes can provide insights into critical cellular processes including vesicle trafficking, cyto-skeletal rearrangement, nuclear events, and even cell death. In this respect, fluorescent chemical probes are key tools that can allow visualization of phospholipid dynamics in live cells. We report peptide-based ratiometric fluorescent sensors for detecting phosphoinositides, phospholipids which regulate various cell signaling events. The probes are readily cell permeable and light up phosphoinositides present in cellular and some subcellular membranes. We hope that the ease of cellular incorporation and quantifiable fluorescence response will make our probes apt for imaging phosphoinositide dynamics in vivo and are working toward this goal. (Read Mondal’s article DOI: 10.1021/acschembio.6b00203)
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DANIELLE SCHMITT
Image courtesy of Danielle Schmitt.
Education: Ball State University, Muncie, Indiana, B.S. in Chemistry, 2012; University of Maryland Baltimore County Ph.D. Candidate in Chemistry, Research Advisor: Prof. Songon An Current Position: Graduate research assistant at the University of Maryland Baltimore County Nonscientific Interests: Reading, music, visiting friends and family My Ph.D. research focuses on the spatiotemporal regulation of metabolic complexes. I have investigated the cellular dynamics of the enzymes catalyzing de novo purine biosynthesis inside living human cells. In my current work, I have investigated the effect of AMPK signaling networks on de novo purine biosynthesis in live cells using time-lapse fluorescence singlecell microscopy. After activating AMPK in cells, I found that only one enzyme of de novo purine biosynthesis formed cytoplasmic “self-assemblies” which excluded other pathway enzymes. Furthermore, the observed self-assembly is associated with decreased cellular levels of purine metabolites. Therefore, we propose that the selective sequestration of just one purine biosynthetic enzyme provides a downregulation mechanism for purine biosynthesis. (Read Schmitt’s article DOI: 10.1021/ acschembio.6b00039)
THERESA NEUMANN
Image courtesy of Patrick Waßmer.
Education: University of Bayreuth, B.Sc. in Chemistry 2010; Technical University of Darmstadt, M.Sc. in Chemistry 2013 1766
DOI: 10.1021/acschembio.6b00577 ACS Chem. Biol. 2016, 11, 1765−1768
ACS Chemical Biology
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Introducing Our Authors
XI SHI
Sanofi-Aventis, Vitry sur Seine France, Research Advisor: Dr. H. Minoux. Current Position: Institut de Chimie de Nice, Université Nice Sophia Antipolis, Nice France, postdoctoral researcher since February 2016 Nonscientific Interests: Horseback riding, hiking, reading, wine and spirits I am particularly interested in revealing biomolecular mechanisms at spatial and temporal scales that remain difficult to observe experimentally, using so-called computational microscope methods. Flexibility plays a key role in ligand receptor recognition processes. In this paper, we present the discovery of unusual conformations of a blood epitope which allow binding to the pathogen Ralstonia solanacearum lectin. I was immediately fascinated by this project focused on finding and describing hidden conformations of this fucosylated oligosaccharide. Lewis x is present in human tissues and serves as an anchor for several pathogens. The characterization of opened conformations is of paramount importance in order to design competitive binders for preventing bacterial recognition, adhesion, and then infection. (Read Topin’s article DOI: 10.1021/acschembio.6b00333)
Image courtesy of Xi Shi.
Education: University of Rochester, Ph.D. in Pharmacology, 2011, Advisor: Bradford Berk Current Position: Scientist I, Feng Zhang lab; Jen Pan group, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard Nonscientific Interests: Cooking, traveling, and reading My research interests include studying the signaling pathways involved in human psychiatric diseases such as bipolar and schizophrenia, identifying new therapeutic target for the treatment. In this manuscript, we hypothesized the traditional mood stabilizer, lithium, exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3). Using high-throughput screening campaign, we identified novel highly selective and potent GSK3 inhibitors, which attenuate amphetamine-induced hyperactivity in mice. GSK3 plays an important role in many human diseases, such as noninsulin-dependent diabetes, cardiac hypertrophy, cancer, and neural disorders. Identifying highly selective and potent GSK3 inhibitors provides a new way to dissect the function of GSK3 isoforms (GSK3α and GSK3β) in multiple disease signaling pathways. (Read Shi’s article, DOI: 10.1021/acschembio.6b00306)
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PETER MAN-UN UNG
Image courtesy of Nickolay Khazanov.
JÉRÉMIE TOPIN
Education: University of California, San Diego, B.S. in Pharmacological Chemistry, 2006, Advisor: J. Andrew McCammon; University of Michigan; Ph.D. in Medicinal Chemistry, 2013, Advisor: Heather Carlson; Icahn School of Medicine at Mount Sinai; Postdoctoral fellow, 2015, Advisor: Avner Schlessinger Current Position: Research scientist, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, with Prof. Avner Schlessinger Nonscientific Interests: Traveling; ballroom and social dancing − Zouk, West Coast Swing, Bachata; portrait, action, and fashion photography Protein−ligand complexes are dynamic, with both the protein and ligand adopting an ensemble of conformations that are important for their recognition. In this manuscript, we analyze the structures of various sugar transporters and construct a homology model of the human GLUT1 transporter in an occluded conformation. We identify a novel cryptic pocket and demonstrate the relevance of this pocket through site-directed mutagenesis. Furthermore, using structure-based virtual screening we are able to identify multiple novel small molecules with high affinity for GLUT1 that may target the cryptic pocket. (Read Ung’s article DOI: 10.1021/acschembio.6b00304)
Image courtesy of Caroline Bushdid.
Education: M.Sc. at Université Joseph Fourrier, Grenoble France; Ph.D. at Institut de Chimie de Nice, Université Nice Sophia Antipolis, Nice France, Research Advisors: Pr. S. Antonczak and Pr. J. Golebiowski; Postdoctoral researcher at CERMAV, Université Joseph Fourier, Grenoble France Research Advisor: Dr. A. Imberty; Postdoctoral researcher at 1767
DOI: 10.1021/acschembio.6b00577 ACS Chem. Biol. 2016, 11, 1765−1768
ACS Chemical Biology
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Introducing Our Authors
SOMSINEE WISITPITTHAYA
Image courtesy of Joseph A. Haegele.
Education: Chulalongkorn University, Thailand, B.A. Chemistry, 2010 with Assistant Professor Yongsak Sritana-Anant Current Position: Cornell University, Chemistry and Chemical Biology Department, Graduate Student with Professor Yimon Aye Nonscientific Interests: Cooking, baking, swimming, and hiking My research focuses on understanding the inhibitory modes of nucleotide chemotherapeutics on the enzyme ribonucleotide reductase (RNR). RNR catalyzes the rate-determining step in the de novo dNTP biosynthesis required for DNA replication and repair. Many successful anticancer nucleotides in clinical use target this enzyme as a means to prevent cancer cell proliferation. However, these agents not only target RNR but also induce various nondesirable off-target effects. In this article, through characterizations of the modes of action of cladribine and fludarabine, we discovered that ligand-induced protein hexamerization is a common mode of reversible RNR inhibition and plays a role in drug resistance mechanisms. This generality offers a new avenue to allosterically regulate one of life’s most essential enzymes, paving the way to novel small-molecule-based RNR-targeted interventions. (Read Wisitpitthaya’s article DOI: 10.1021/acschembio.6b00303)
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DOI: 10.1021/acschembio.6b00577 ACS Chem. Biol. 2016, 11, 1765−1768
