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Identifying chemical combinations to expand the TB-drug pipeline

Friday, October 25, 2019 - 3:10pm

Don Ronning

Don Ronning

Department of Chemistry & Biochemistry, The University of Toledo

(Anderson)

Tuberculosis is responsible for 1.5 million deaths each year. This is more than any other infectious disease caused by a single pathogen and no new first-line drugs for TB have entered the clinic in more than 50 years. My group combines structure/function relationship studies on Mycobacterium tuberculosis drug targets with library screening to improve the TB drug pipeline. The complementary tools of X-ray crystallography and enzyme kinetics/inhibition studies form the basis for identifying new TB-active compounds as well as the characterization of known anti-tubercular compounds with ambiguous mechanism-of-action. In particular, our studies have clarified the mechanism-of-action of Isoxyl, Thiacetazone, and Ebselen anti-bacterial activity against M. tuberculosis and shown that covalent modification of cysteine residues on bacterial protein targets is a valuable inhibitory mechanism. This presentation will discuss how we are applying that understanding and building upon those observations to develop second-generation, dual-function covalent inhibitors of mycobacterial mycolyltransferases. Preliminary results suggest that these compounds function synergistically with b-lactams in non-pathogenic mycobacteria and we are working to understand the mechanistic basis of this apparent synergy. Read more about Identifying chemical combinations to expand the TB-drug pipeline

Nuclear Spin Hyperpolarization from Parahydrogen and Heterogeneous Catalysis by Clifford Russell Bowers, Department of Chemistry, University of Florida

Friday, November 8, 2019 - 3:10pm

Clifford Russell Bowers

Clifford Russell Bowers

Department of Chemistry, University of Florida

(Huang)

Nuclear spin singlet-states are attracting a lot of attention nowadays because they can significantly extend the useable lifetime of hyperpolarization. Singlet order decays more slowly than ordinary magnetization because the former is protected from the intra-pair dipole-dipole relaxation mechanism. Singlet-triplet imbalance (STI), which refers to the population differential between the singlet and triplet manifolds for a pair of strongly coupled spin-1/2 nuclei, can be prepared directly from parahydrogen, the singlet spin isomer of dihydrogen that is easily generated by cooling the gas in the presence of an ortho-para conversion catalyst. With perfect magnetic equivalence and isolation, the parahydrogen singlet is the quintessential long-lived state with a lifetime of many weeks. The transformation of singlet order into observable Zeeman order can be achieved by symmetry breaking chemistry.1 The key requirement is pairwise addition with retention of inter-pair spin-spin coupling. This talk will survey some highlights from our recent research utilizing heterogeneous catalysis to convert dihydrogen STI into magnetization on various target molecules in gases and solution. One of the main challenges that needs to be overcome is the fast diffusion of H ad-atoms that is typically observed on the catalytically active metal surfaces. We show that through rational design of heterogeneous catalysts, significant improvements can be made in the efficiency of the singlet-to-magnetization transformation.2-3 Three examples are presented: ultra-low loadings of Pt on shaped cerium oxide nanocrystal supports, PtSn intermetallic nanoparticles for hyperpolarization of water and alcohols, and certain other bimetallic combinations that have delivered substantially higher performance than monometallic nanoparticle catalysts. Lastly, a new approach utilizing heterogeneous catalysis for the continuous-flow synthesis of symmetric and pseudo-symmetric parahydrogen adducts hosting long-lived states will be presented.

Acknowledgements: NSF grants CHE-1808239 (CRB and WH), CBET-1933723 (HH-W and CRB) and the NHMFL-UCGP which is supported by the National Science Foundation Cooperative Agreement No. DMR-1644779 and the State of Florida.

1. CR Bowers, DP Weitekamp, PRL, 1986; CR Bowers, DP Weitekamp, JACS, 1987

2. Evan Wenbo Zhao, Raghu Maligal-Ganesh, Yong Du, Tommy Yunpu Zhao, James Collins, Tao Ma, Lin Zhou, Tian-Wei Goh, Wenyu Huang, Clifford R Bowers - Chem, 2018

3. Evan W Zhao, Raghu Maligal‐Ganesh, Chaoxian Xiao, Tian‐Wei Goh, Zhiyuan Qi, Yuchen Pei, Helena E Hagelin‐Weaver, Wenyu Huang, Clifford R Bowers -Angew. Chem. 2017 Read more about Nuclear Spin Hyperpolarization from Parahydrogen and Heterogeneous Catalysis by Clifford Russell Bowers, Department of Chemistry, University of Florida

Investigating Electrostatic Mechanisms of Membrane Organization and Function

Friday, January 24, 2020 - 3:10pm

Lauren Webb


Lauren Webb


Department of Chemistry, The University of Texas at Austin


(VanVeller)


Abstract:  Lipid bilayer membranes are complex, dynamic, and functional structures composed of a wide diversity of lipids, proteins, small molecules, and water organized in heterogeneous domains through noncovalent interactions. The structure and motion of these molecules generate large electric fields within the interior of the membrane that are critical to membrane structure and function.  Here, we describe how vibrational spectroscopy of unnatural nitrile chromophores places throughout the membrane structure is used to measure electrostatic fields in peptides intercalated in free-standing lipid bilayer membranes of increasing chemical complexity.  In combination with electrodynamics simulations, these experiments highlight how common small molecules such as cholesterol dramatically affect membrane structure and dynamics through large changes to membrane electric fields.  

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New Developments in Mass Spectrometry-based Metabolomics

Friday, December 6, 2019 - 3:10pm

Facundo Fernandez

Facundo Fernandez

Georgia Institute of Technology

(Lee)

Abstract

he highly dynamic nature of metabolites and their abundances makes metabolomics a powerful endpoint of the ‘omics’ cascade, yielding a molecular profile that is closest to the physiological phenotype. Metabolomic profiles are therefore sensitive to subtle perturbations observed in early disease stages or disease progression, which may be difficult to detect at the proteome or transcriptome levels. Human diseases are multi-factorial in nature, and studying small parts of their associated molecular changes is generally insufficient for understanding the full spectrum of disease phenotypes.

The metabolome is the total collection of biologically-active small molecules with molecular weights lower than about ~1.5 kDa in an organism. This includes endogenous molecules that are biosynthesized by metabolic networks in “primary metabolism”, specialized “secondary metabolite” signaling or defense molecules, molecules derived from diet or environmental exposures (the exposome), and molecules derived from the biosynthetic interactions with associated microbes (the microbiome). Metabolomics can either be “targeted” to a set of known compounds, for example certain lipids, or “non-targeted”, which attempts to detect and relatively quantify as many metabolites as possible.

The vast chemical diversity of the metabolome (lipids, sugars, amino acids, etc.), and its wide dynamic range (mM to fM) implies that no single analytical method can adequately profile all metabolites in one metabolomics experiment. Along these lines, the “fusion” of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) is emerging as one of the most powerful avenues to increase metabolome coverage. Nested separations that work in a time frame compatible with mass spectrometry, such as those performed by ion mobility, are also playing a key analytical role in metabolomics as a way of increasing peak capacity, and identifying metabolites through ion mobility collision cross section measurements. Further, localization of metabolites at the tissue level with imaging mass spectrometry experiments, allows linking their abundance with changes observed in biofluids. In this seminar, I will highlight progress along these various fronts, with emphasis on the detection, screening and treatment of complex diseases such as prostate and ovarian cancer, and cystic fibrosis. Read more about New Developments in Mass Spectrometry-based Metabolomics

Site-selective protein modification with homogeneous transition-metal catalysts by Zachary Ball, Department of Chemistry, Rice University

Friday, November 15, 2019 - 1:10pm

Zachary Ball

Zachary Ball

Department of Chemistry, Rice University

(VanVeller)

Chemists are fascinated by metalloenzymes and their chemistry. The reactivity and selectivity of enzyme processes would be powerful practical advances if harnessed in designed transition-metal catalysts. But designing enzyme-like catalysts from scratch has proven exceedingly challenging. Substrate selectivity in polyfunctional environments and highly reactive intermediates incompatible with the bulk aqueous media are properties that are typically too complex and challenging to replicate in simplified, designed systems. Our own efforts have taken advantage of diverse concepts, such as molecular recognition, biomimetic assembly, and structure–function relationships to pursue new methods for site-selective chemistry. Read more about Site-selective protein modification with homogeneous transition-metal catalysts by Zachary Ball, Department of Chemistry, Rice University