Weekly: LART 106 – 1:30 pm to 2:20 pm
Friday, November 17, 2017
Tudor Firica, Cornell Lab, Boise State University, Department of Chemistry & Biochemistry
Title: “Borrelia burgdorferi Glycosaminoglycan Binding Protein (Bgp) as a Potential Antibiotic Target”
Lyme disease is a tick-transmitted illness caused by the spirochaete Borrelia burgdorferi. If left untreated, Lyme disease can lead to serious health problems such as paralysis, muscle weakness, and inflammation of the joints. In 2015, the CDC reported over 30,000 confirmed cases of Lyme disease in the U.S. Although there are existing antibiotics for Lyme disease; such as doxycycline, amoxicillin and cefuroxime axetil; some patients display intolerance to these treatments. Here we report the development of alternative drugs that target Borrelia Glycosaminoglycan-binding Protein (BGP). BGP is one of three known Borrelia MTA/SAH nucleosidases (MTNs), and a key component in the methionine salvage pathway, an essential part of Borrelia burgdorferi metabolic activity. Novel BGP inhibitors were identified from in silico screening of drug databases using an E. coli MTN template. A series of subsequent compounds were synthesized based on the lead compounds, and their inhibitory activity against purified recombinant BGP assessed using spectrophotometric enzyme assays. Several of the compounds show promising anti-BGP activity and in vitro antibiotic activity against Borrelia cultures. This work provides the basis for further development of these drugs as novel Lyme disease treatments.
Steve Nick, Cornell Lab, Boise State University, Department of Chemistry & Biochemistry
Title: “The Effects of Doxorubicin on Cardiac Fibroblast Function”
Doxorubicin (DOX) is a highly effective chemotherapeutic used to treat many adult and pediatric cancers such as solid tumors, leukemia, lymphomas, and breast cancer. However, its use is limited due to dose-dependent cardiotoxicity, which can lead to lethal cardiomyopathy. The toxic effects of DOX on cardiomyocytes have been studied extensively. However, the effects of DOX on cardiac fibroblasts, the largest cell population in the heart, are largely unknown. Cardiac fibroblasts are responsible for maintaining the extracellular matrix (ECM) of the heart. In addition to being a support structure, the cardiac ECM traffics growth factors and cytokines, contributes to blood vessel formation, and allows for electrical signaling. In this study, primary cardiac fibroblasts isolated from BALB/c mice were treated with DOX to survey the change in gene expression of ECM and adhesion proteins, specifically collagen and matrix remodeling proteins. A DOX treatment of 1 µM caused 70-80% cell viability; this concentration was used for further experiments to simulate DOX pressure. RT-qPCR was used to detect changes in mRNA gene expression following DOX treatment. Results indicated that genes for collagen experienced an overall decrease in mRNA expression and the genes for matrix metalloproteinases (MMPs), which degrade collagen, increased in expression. Future experiments will utilize tandem mass tags to analyze the protein expression of cardiac fibroblasts using LC-MS-MS. This data will be used to confirm the results from RT-qPCR. Exploring the impact of DOX on cardiac fibroblasts and the cardiac ECM remodeling pathways will ultimately assist in further chemotherapeutic research aimed at reducing the cardiotoxic side effects of DOX.
Friday, November 10, 2017
Wyatt Meyers, Cornell Lab, Boise State University, Department of Chemistry & Biochemistry
Title: “Study of Inhibition of the Borrelia burgdorferi Cytoplasmic MTA/SAH Nucleosidase-Pfs”
Borrelia burgdorferi, the pathogen that causes Lyme disease, is transmitted predominately by the hard-bodied ticks Ixodes scapularis, Ixodes pacifiicus, Ixodes ricinus, and Ixodes persulcatus. Lyme disease is the most common vectorborne disease in the United States, with CDC estimating annual cases occurring in as high as 365,000 persons. Doxycycline, amoxicillin and cefuroxime axetil are the current treatments that have shown to be effective, though resistance is rising. A series of drugs referred to as the JT, have shown promise in inhibiting the activity of the Nucleosidase Pfs. Pfs is vital in the metabolic activity of Borrelia burgdorferi, exhibited by MTA/SAH nucleosidase activity; which is a component in the methionine salvage pathway. Four drugs from this series, JT-15, JT-17, JT-19, and JT-22, have shown promise as inhibitors. Kinetic analyses series of enzymatic activity finding that 58%, 50%, 52%, and 82% reductions in Pfs specific activity, respectively. The inhibitory effectiveness of this series is being explored for use in treating patients with resistance to primary treatments, as chronic Lyme disease (caused by resistant strains) can present joint pain and swelling, speech problems, loss of short term memory, and continuous fatigue.
Friday, November 3, 2017
Dr. Owen McDougal, Boise State University, Department of Chemistry & Biochemistry
Title: “Natural Products: From Food to Fatal”
Friday, October 27, 2017
Meagan Boll, Boise State University, Department of Chemistry & Biochemistry
Title: “Metabolic Impact of MtnN Deficiency: A Proteomic Analysis”
Jonathan Prince, Boise State University, Department of Chemistry & Biochemistry
Title: “An Investigation Into the Accuracy of Inversion Barriers Derived From the Weizmann Methods”
Friday, October 20, 2017
Allal Laaraj, Boise State University, Department of Chemistry & Biochemistry
Title: “Designing Chemotherapy Drugs with Potentially Fewer Side Effects”
Friday, October 13, 2017
Daniel Shin, Master of Science Program, Boise State University, Department of Chemistry & Biochemistry
Title: “AHL based Modulators for RhlI, a Quorum Sensing Signal Synthase in P. aeruginosa”
Gram-negative bacteria use N-acyl homoserine lactone (AHL) autoinducer based signal system, known as quorum sensing (QS), to modulate the gene expression for such traits as biofilm formation, toxin production, and antibiotic resistance. Therefore, there is great potential in pursuing quorum sensing inhibition (QSI) as a means of achieving antivirulence. Pseudomonas aeruginosa, an opportunistic pathogen commonly found in healthcare-related infections, use two LuxI/R type systems to regulate AHL-based quorum sensing, LasI/R and RhlI/R. LasI (initiator protein/signal synthase) and LasR (receptor) use 3-oxododecanoyl homoserine lactone signal molecule while RhlI and RhlR use butanoyl homoserine lactone autoinducer. Thus far, most of the studies have focused on inhibiting the Las system, in particular by using AHL signal analogs to interfere with signal-receptor binding. Recently, RhlI/R system has gain attention as potentially having greater effect in P. aeruginosa virulence. In this study, we have tested the effect of AHL analogs on RhlI, as product inhibitors with the goal of targeting both RhlI and RhlR for increased potency. Screening of compounds have revealed three variations to have the great effect on RhlI inhibition: longer/bulkier acyl- chain, D-stereocenter in the headgroup, and a less polar thiolactone head-group. Surprisingly, the addition of a carbonyl at the C3 position was found to activate the enzyme. Moreover, we measured kinetic constants of RhlI with various acyl-substrates and performed inhibition assays with inert acyl-substrate analogs to determine how RhlI activity changes to variations in the acyl-chain length. We found that the catalytic efficiency of acyl-substrate and inhibition potency of the corresponding inert acyl-substrate analogs surges with increase in the length of the acyl-chain. These patterns suggest that long acyl-chains most likely bind to an alternate binding site with marked increase in both kon and koff rate constants. Our findings with AHL derivatives provide a basis for rational design of quorum sensing inhibitors to better combat P. aeruginosa bacterial infections.
Friday, October 6, 2017
Lisa M. Berreau, Executive Associate Dean and Professor, Utah State University, Department of Chemistry & Biochemistry
Title: “Visible Light-triggered Hydroxyflavones for Carbon Monoxide Delivery”
Carbon monoxide (CO) is of intense current interest as a potential therapeutic. This is due to pre-clinical studies that have demonstrated the beneficial health effects of this gaseous molecule, including its dose-dependent anti-hypertensive, anti-inflammatory and cell protective effects. To date, studies of the biological effects of CO have been performed almost exclusively using variable concentrations of CO gas or metal carbonyl-based CO-releasing molecules (CORMs). These approaches have limitations, including control over the rate, location and amount of CO released. To address the need for the delivery of precise amounts of CO, particularly for studies of the dose-dependent biological effects of this molecule, non-metal compounds that release CO only upon exposure to light (photoCORMs) are being developed. Our laboratory is investigating the use of biologically-inspired extended flavonols as visible light-triggered CO releasing molecules. This seminar will focus on recent studies that show that an extended flavonol motif is highly tunable for CO delivery. Specific areas of investigation to be discussed include: (1) tuning the CO release properties of flavonols via heavy atom effects; (2) solution properties of an extended flavonol and its interactions with albumin proteins; and (3) a sense-and-release flavonol that probes cellular thiol concentrations prior to light-triggered CO release.
Friday, September 29, 2017
Terry Gilton, Assistant Clinical Professor, Boise State University, Department of Chemistry & Biochemistry
Title: “Chemistry in Two Dimensions: The Role of Substrate Photoelectrons in the UV Photochemistry of Physisorbed Methyl Halides”
The ultraviolet surface photochemistry over the range of 351nm to 193nm, and adsorption behavior of several physisorbed methyl halides was studied on Ni(111), with the particular goal of understanding the role of substrate photoelectrons. Comparison of fragment time-of-flight yields, as a function of surface coverage and laser wavelength, with known gas-phase behavior, showed that the photochemistry of some of these molecules was dominated by dissociative electron attachment of low kinetic energy substrate photoelectrons. Direct photofragmentation was observed at coverages above 1 monolayer for laser wavelengths which the molecules absorb in the gas phase. CH3Cl exhibited a dissociative electron attachment of substrate electrons which, at its maximum, had a cross section four orders of magnitude larger than the analogous process in the gas phase.
Photolysis of CH3Cl and other methyl halides was also studied on spacer layers of water, xenon, and hexane. The spacer was found to affect the energy of the ejected fragments only slightly, but affected the yield of fragments profoundly. The work function of the Ni/spacer system is shown to correlate with the yield: if the work function is above the energy of the incident photon no fragmentation is observed, if it is below this energy fragmentation is observed. The fragment intensity was observed to increase markedly as the photon energy increases beyond the work function.
Friday, September 22, 2017
Henry Charlier, Associate Professor, Boise State University, Department of Chemistry & Biochemistry
Title: “A Presentation Pertaining to Preparing Pertinent, Purposeful, Pleasantly Pretty, Powerful, and Passionate Power Point Presentations that Will Particularly Please All Present People”
Friday, September 15, 2017
Ashley Poppe, Boise State University, Graduate Student
Title: “Acyl-substrate Recognition in the Binding and Chemical Steps of BmaI1 in Burkholderia mallei”
Many bacterial pathogens use quorum sensing as an intercellular communication mechanism to regulate virulence gene expression. This mechanism gives the bacteria an advantage to colonize host defenses and express antibiotic resistance. Disrupting quorum sensing is a promising strategy to disrupt interbacterial communication and mitigate resistance towards antibiotics. AHL synthase uses acyl-ACP and S-adenosyl-L-methionine (SAM) to synthesize N-acyl-L-homoserine lactones (AHLs) quorum sensing signals in Gram-negative bacteria. BmaI1 is the AHL synthase in Burkholderia mallei; the bacteria responsible for causing glanders disease. BmaI1 specifically uses octanoyl-ACP and S-adenosyl-L-methionine (SAM) to create octanoyl-homoserine lactone (C8-AHL) native quorum signal for this bacterium. This project is aimed at understanding the extent of acyl substrate recognition in binding and chemical steps of BmaI1 catalyzed AHL synthesis. In this talk, I will describe tools developed in our laboratory to investigate substrate recognition at each enzymatic step in AHL synthesis. Inhibition of AHL synthesis is a promising strategy to disrupt interbacterial communication and curb virulence gene expression in Gram-negative bacteria. Discovering how BmaI1 is able to selectively recognize octanoyl-ACP will give insight into designing quorum sensing specific inhibitors for this pathogen.
Friday, September 8, 2017
Kelsey Skluzacek, Boise State University, Graduate Student
Title: “Structure-Based Drug Design of Novel Therapeutics Targeting Metastatic Breast Cancer”
It is estimated that in 2017, over 300,000 individuals will be diagnosed with breast cancer and more than 40,000 of those will lose their life. The five-year survival rate prior to metastasis is quite promising at 93%, whereas, after metastasis that rate plummets to an abysmal 23%. Inflammatory cytokines (ICs) have been shown to play a role in the early stages of metastasis, leading to an interest in developing small molecule inhibitors (SMIs) of the proteins responsible. Previous work used computational chemistry to scan the surface of the ICs and located potential binding sites. Out of 260,000 computationally screened compounds, 16 compounds projected to have the tightest binding were chosen to be synthesized and tested. These 16 compounds were obtained from the National Cancer Institute and further screened for inhibition of the STAT3 signaling pathway by an enzyme-linked immunosorbent assay (ELISA) of phosphorylated STAT3 (pSTAT3). It was found that SMI-8, SMI-10, and SMI-11 would potentially have the greatest inhibitory effects on IC signaling. The goal of this project is to synthesize analogs of SMI-8 and SMI-10 to produce second-generation compounds with an even greater propensity of disrupting pathways that lead to breast cancer metastasis.
Friday, September 1, 2017
Jennifer Eichmeyer, MS, LCGC, Boise State University, College of Health Sciences/School of Allied Health Sciences
Title: Learn about the Field of Genetic Counseling!
Genetic counselors are health care professionals who help individuals and their families learn about the effects of genetic conditions and common diseases. By tracing family history and evaluating test results, genetic counselors identify individuals at risk and provide information so families can learn how to manage their health. There are a variety of career settings that serve many different people such as practice in a private clinics or large hospitals. There are also options to work in a clinical laboratory or contribute to policy advocacy. New and different opportunities regularly become available as the field continues to grow. Genetic counselors earn a professional-level salary and benefit from rewarding careers. Through graduate-level courses and clinical training genetic counselors earn a highly respected Master’s degree. Programs prepare graduates to seek professional certification and launch them into one of the most personally satisfying careers in the health sciences.
Jennifer graduated from Iowa State University with a BS in Genetics and University of Texas at Houston with MS in Genetic Counseling. She started her career in Idaho as a genetic counselor in 2002 at St. Luke’s Health System and established the first cancer genetic counseling clinic for the state. Jennifer has been involved in expanding other genetic services in the state of Idaho through the development of a High Risk Breast Clinic, NICU genetics, launching telehealth genetic counseling services, and was involved in successfully getting state licensure for genetic counselors passed in the Idaho legislature. Jennifer was hired at Boise State in June to develop and administer the MS Genetic Counseling program.