Introducing Our Authors pubs.acs.org/acschemicalbiology
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ALEX CHAPMAN
Biology, MRes/Ph.D. cosupervised by Prof. Ed Tate and Dr. Ernesto Cota, 2014. Nonscientific interests: Cricket, music, food During my Ph.D., I have used several biophysical and structural methods to explore the structural and dynamic details of a protein−protein interaction involved in the motility of the human malaria parasite. I am particularly interested in using the information obtained by such experiments to design molecules that might reliably perturb such a complex biological system. In this work, we used the interactionmediated by a single helix of one protein that gets fully buried by its partneras a template for the design and synthesis of constrained helical peptide inhibitors. Via resolution of three cocrystal structures, we were able to make a structural comparison of state-of-the-art helix constraint technologies and moreover show for the first time that such buried protein−protein interactions may be targeted by these classes of molecule. (Read Douse’s article, DOI: 10.1021/cb500271c.)
Image courtesy of Alex Chapman.
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Education: Oberlin College, B.A. Chemistry, 2010; Colorado State University, Ph.D. candidate with Professor Brian R. McNaughton Nonscientific interests: Lacrosse, hockey, fishing, and hiking Increased cellular levels of protein−protein interactions (PPIs) involving ankyrin repeat proteins are linked to various human diseases, including multiple cancers. One such set are PPIs involving the ankyrin repeat gankyrin. By virtue of the relatively featureless putative binding face of gankyrin, and large surface areas involved in gankyrin-dependent PPIs, these complexes largely evade disruption by traditional small molecule reagents and drugs. Synthetic proteins represent a potential solution to the general challenge of inhibiting disease-relevant PPIs. My research interests center on the discovery of proteins that inhibit gankyrindependent PPIs and modulate gankyrin-dependent oncogenic biochemistry, cell function, and cell fate. Toward that goal, in this article we describe two new gankyrin-binding proteins, which were identified by screening a ∼5 × 109 library of resurfaced proteins, using split-superpositive Green Fluorescent Protein reassembly. These proteins represent starting pionts for the development of protein basic research tools and drug leads, which target gankyrin. (Read Chapman’s article, DOI: 10.1021/cb5003834.)
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Image courtesy of Rosanna Betancourt.
Current position: Vanderbilt University, Program in Chemical and Physical Biology and Vanderbilt Center for Neuroscience Drug Discovery, Ph.D. candidate, Advisor: Prof. Craig Lindsley. Education: Universidad de Costa Rica, Costa Rica, Pharm.D., 2009; Universidad de Costa Rica, M.Sc in Chemistry, 2012, with Prof. Guy V. Lamoureux and Prof. Alice L. Perez. Nonscientific interests: Playing pool, guitar, soccer, gardening, cooking. I am very interested in medicinal chemistry and development of tool molecules to study the biology of the brain. My current project involves the design and optimization of selective mGlu1 positive allosteric modulators (PAM) with good pharmacokinetic properties for target validation studies. Many genes have been implicated in the etiology of schizophrenia, but for many of them little is known about their therapeutic relevance. We report the pharmacological characterization of mutant mGlu1 isoforms overrepresented among schizophrenics. Most of these mutations disrupted the functionality of mGlu1, indicating that restoring the receptor activity might have a therapeutic benefit. As no optimal probes were available to answer this question, we embarked
CHRISTOPHER H. DOUSE
Image courtesy of Christopher H. Douse.
Education: Wadham College, University of Oxford, MChem in Chemistry, 2009; Imperial College London Institute of Chemical © 2014 American Chemical Society
́ PEDRO M. GARCIA-BARRANTES
Published: October 17, 2014 2173
dx.doi.org/10.1021/cb500786f | ACS Chem. Biol. 2014, 9, 2173−2175
ACS Chemical Biology
Introducing Our Authors
Location: Thurston Anticancer Drug Discovery Research Group, King’s College London, U.K. Education: Ph.D. in Computational Drug Design, King’s College London, 2014 (Supervisor: Prof. David E. Thurston) Nonscientific interests: Football, reading, cooking, traveling My research interests lie in the use of molecular dynamics simulations and other in silico techniques to direct drug discovery. I am particularly interested in targeting oncogenic transcription factors at both the protein−DNA (PDI) and protein−protein interfaces (PPI) using small molecules. The pyrrolobenzodiazepines (PBDs) are a family of guanine-specific DNA minor-groove binding agents that cause DNA strand breaks, and thus apoptosis, and can also inhibit transcription factor binding. The most cytotoxic members of the PBD monomer family are glycosylated, and we have shown that this occurs due to the enhanced hydrogenbond-mediated DNA sequence selectivity of the molecules and the consequent steric blocking of the interaction of specific transcription factors. This is an important observation for the future design of minor-groove binding agents and suggests that the introduction of bulky groups at specific locations in molecules may prevent the binding of certain oncogenic transcription factors to DNA. (Read Jackson’s article, DOI: 10.1021/cb5002203.)
on the development of novel mGlu1 PAMs to assess the feasibility of chemical modulation in these mutants. (Read Garcia-Barrantes’ article, DOI: 10.1021/cb500560h.) JOSEPH P. GERDT
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Image courtesy of Joseph Gerdt.
Current position: Postdoctoral Research Fellow, Harvard Medical School with Prof. Jon Clardy. Education: University of Illinois at UrbanaChampaign, B.S. Chemistry, 2008; undergraduate research with Prof. Scott Silverman; University of WisconsinMadison, Ph.D. Chemistry, 2014 graduate research with Prof. Helen Blackwell. Nonscientific interests: Reading, watching and playing sports, serving in my church. The topic of antibiotic resistance has intrigued me since early on in college. I wondered, how can these microbes adapt to every new drug we try, and is there a way to “outsmart” them? Upon joining the Blackwell group at UWMadison, I read many papers suggesting that resistance might spread less quickly to small molecules that target a form of bacterial communication called quorum sensing; however, little experimental work had directly tested this hypothesis. This manuscript reports my study at the interface of chemical biology, microbiology, and evolutionary biology that demonstrates that two unique obstacles impede the spread of resistance to quorum-sensing inhibitors. This work provides firm empirical evidence to motivate the development of improved quorum-sensing inhibitors that could potentially find use as resistance-robust therapeutics. I am currently studying the fascinating and related topic of how microbial species residing in complex communities cooperate and compete with each other using secreted small molecules. (Read Gerdt’s article, DOI: 10.1021/cb5004288.) PAUL JACKSON
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PRAVIN MUTHU
Image courtesy of Pravin Muthu.
Current position: Working on Doctorate in Chemistry, Emory University, Department of Chemistry, Advisor: Dr. Stefan Lutz Education: Masters in Chemical Engineering, Johns Hopkins University, Department of Chemical Engineering, Advisor: Dr. Jeffrey Gray; Bachelors in Chemical Engineering, Johns Hopkins University, Department of Chemical Engineering, Advisor: Dr. Jeffrey Gray Nonscientific interests: Board games, tennis, and eating new foods. My work focuses on designing biocatalysts to have specialized properties for applications in chemicals production and therapeutic proteins. More specifically, I adapt concepts from applied mathematics to optimize a protein sequence for an arbitrary function. In this issue’s article, our lab designed a selective reporter gene for use in positron emission tomography (PET). We wanted to invert the native D-nucleoside preference of human deoxycytidine kinase to instead favor an unnatural L-nucleosidic PET radiolabel. We first developed a statistical model to predict favorable amino acid substitutions, and then iteratively produced improved kinase variants through two rounds of experimental validation. This approach ultimately resulted in an orthogonal kinase variant with improved activity
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Image courtesy of Paul Jackson.
Current position: Postdoctoral Research Associate 2174
dx.doi.org/10.1021/cb500786f | ACS Chem. Biol. 2014, 9, 2173−2175
ACS Chemical Biology
Introducing Our Authors
Education: The University of Tokyo, B.S. in Biology, 2010; The University of Tokyo, M.S. in Medical Science with Prof. Nobutaka Hirokawa, 2012. Nonscientific interests: Reading, music, quality Japanese animations My research interests include the modulation of cell functions by light with minimum invasion. To realize the photocontrol of physiological functions in living cells, various caged compounds have been developed and widely used. In this area, one of the important problems is to develop caged compounds that can be activated by longer-wavelength light, which is less cytotoxic and has high tissue penetration. As described in our manuscript, we discovered a novel photoreaction that the boron dipyrromethene (BODIPY) fluorophore can function as a caging group for phenol groups under irradiation of blue-green visible light (∼500 nm). Making use of this BODIPY caging group, we developed BODIPY-caged histamines and succeeded in the photostimulation of living HeLa cells. (Read Takahashi’s article, DOI: 10.1021/cb500525p.)
for the PET probe, simultaneously reducing activity for natural metabolites. (Read Muthu’s article, DOI: 10.1021/cb500463f.)
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MAIRE F. OSBORN
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Image courtesy of Anton Turanov.
Current position: Postdoctoral Associate with Dr. Anastasia Khvorova, RNA Therapeutics Institute, University of Massachusetts Medical School Education: B.S. Chemistry (Honors), McGill University; Ph.D. Chemistry, University of Oregon (Advisor: Dr. Victoria DeRose) Nonscientific interests: Cycling, coffee, midcentury modern design Cisplatin is a universally prescribed anticancer compound. Drug-induced DNA damage within tumor cells is the accepted mechanism of activity, but we lack a comprehensive picture of global drug targets, which would lend valuable insight into the mechanisms of action and resistance in different tissues. My Ph.D. research examined the interactions between Pt(II) and cytoplasmic RNA. We developed an azide-functionalized Pt(II) compound for facile click fluorescent labeling and isolation of Pt-bound species in vivo. Using this reagent, we demonstrated that rRNA and tRNA are major cytoplasmic targets of cisplatin and mapped Pt(II) localization to functionally critical areas of the ribosome, including domains V and VI rRNA (peptidyl transferase center and sarcin-ricin loop). These discoveries preface a new chapter in the investigation of cisplatin pharmacology. (Read Osborn’s article, DOI: 10.1021/cb500395z.)
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JIARUI WANG
Image courtesy of Jiarui Wang.
Current position: B.S. in Biochemistry, University of Michigan in 2014 and anticipate pursuing doctoral degree Nonscientific interests: Adventurous traveling, mystery movies, a stack of good books, and the amazement of architecture I have been doing independent undergraduate research using single molecule FRET analysis at the University of Michigan in Professor Nils Walter’s group. My research is focused on the kinetics of Bsu preQ1-I riboswitch binding to noncognate ligands as well as the effect of magnesium on its folding pathway. I was invited to write this review paper as a semester project, which exposed me to an intriguing world of enzymology. (Read Wang’s article, DOI: 10.1021/cb5004674.)
HIRONORI TAKAHASHI
Image courtesy of Akihico Morozumi.
Current position: Ph.D. student in the laboratory of Chemical Biology and Molecular Imaging at the University of Tokyo; Advisor: Prof. Yasuteru Urano. 2175
dx.doi.org/10.1021/cb500786f | ACS Chem. Biol. 2014, 9, 2173−2175
