Events Calendar

Structural Characterization of Glycans and Glycopeptides using Charge Transfer Dissociation Mass Spectrometry (CTD-MS)

The development of a fluorescent assay to quantify LAT1 transport

Jacqueline Smith, PhD
Department of Chemistry, Howard University

The Large Neutral Amino Acid Transporter (LAT1) facilitates the transport of large branched and aromatic amino acids and nutrients into cells. LAT1 is ubiquitously expressed throughout the body, with abundant expression in immune cells and at the blood-brain barrier. Due to the high metabolic needs of cancer cells for nutrients as they rapidly proliferate, LAT1 is upregulated in several cancer cells. Silencing or inhibiting LAT1 is lethal to cancer cells, highlighting its promise as a drug target. Despite its significance as a target for cancer therapy, there are relatively few LAT1 inhibitors being investigated clinically. This is likely due to a lack of accessible tools to measure LAT1 transport. Traditional assays rely heavily on radiolabeled substrates, which restrict experimental throughput and accessibility. We have developed a fluorescent assay to measure LAT1 uptake using a tryptophan analog, 6-azatryptophan. This assay measured the transport of 6-azatryptophan in several cancer cell lines, which was dependent on the levels of LAT1 expression. We show that 6-azatryptophan transport was mediated through LAT1 by using LAT1-specific chemical and genetic inhibitors.  Recently we have also developed a cell-free version of this assay.  Future work involves using this assay to identify potential inhibitors of LAT1 as therapeutic agents.

Department Seminar

The Role of Chemistry in Direct Ink Writing of Multifunctional Materials, Structures and Devices

Konstantinos Sierros, PhD 
Mechanical and Aerospace Engineering, WVU

There is currently a burgeoning interest in 3D printing multifunctional materials, structures and devices for a multitude of applications such as  energy, health and space. Direct ink writing (DIW) is a versatile 3D printing method based on room temperature extrusion of shear thinning fluids (aka inks) on digitally predefined substrate locations to deposit complex geometries on a layer-by-layer fashion. In this talk we will discuss the critical role that chemistry plays in DIW . In particular we will be discussing model examples to discuss how precursor chemistry influences ink formulation, printing and post-printing treatments. For example, during ink formulation chemistry plays a crucial role since it influences the fluid’s viscosity and flow properties as well as its curing characteristics. Chemical bonding and surface interactions are also of great importance for realizing stable printing and printed layer adhesion. In many systems, inks undergo chemical reactions after printing (e.g., polymerization and gelation) to transition from a liquid state to a solid structure. In addition, during multimaterial printing (e.g., coaxial DIW) chemistry enables the combination and smooth extrusion of different ink materials in a single step. Finally, the development of ecofriendly inks is another area that we will be discussing in terms of green chemistry approaches to reduce harmful solvents and energy consumption.

Natural Products as Chemical Probes to Understand Biological Mechanisms

Fatima Rivas, PhD
Department of Chemistry, LSU, Baton Rouge, Louisiana

Triple negative breast cancer (TNBC) is one of the most aggressive cancer subtypes, affecting primarily women. This subtype is defined by the absence of estrogen, progesterone, and human epidermal growth factor receptor type 2, which limits the effectiveness of standard targeted therapies and contributes to poor prognosis. Non-selective chemotherapy toxicity, drug resistance, and an overall lack of targeted therapeutic modalities negatively impact patient outcomes, contributing to approximately 150,000 deaths per year and a diminished quality of life. There is therefore an urgent need to discover effective, selective TNBC therapies that improve pathological response and reduce mortality. Prof. Rivas will present how natural products can serve not only as potential lead therapeutic agents against TNBC, but also as chemical probes to uncover the biological targets underlying their selectivity.

Ganoderma lucidum is a medicinal mushroom that produces a range of pharmacologically active compounds, including triterpenoids, lipids, and other small bioactive molecules. Among these, ergosterol peroxide (EP), an endoperoxide-containing triterpenoid, displays anticancer activity in both in vitro and in vivo TNBC models. Our group has shown that EP selectively inhibits TNBC cell models while sparing non-cancerous mammary epithelial cells, yet the molecular basis for this selectivity has remained unclear.

To address this gap, we leveraged EP as a chemical probe to interrogate its mechanism of action, leading to the identification of UBR4 as a novel and previously unrecognized target in TNBC. This discovery reframes EP not simply as a cytotoxic natural product, but as a tool for uncovering druggable vulnerabilities specific to this aggressive cancer subtype. While EP has been generated in gram scale in our laboratory, several challenges continue to limit its preclinical advancement. Herein, we disclose our efforts toward a focused EP analog library, guided by structure-activity relationships around UBR4 engagement, alongside our target identification and validation studies. Together, this work illustrates how natural products can serve a dual role, as chemical probes that illuminate previously undefined biology, and as starting points for the development of targeted therapeutic strategies to support future clinical translation. 

Department Seminar

Pushing the (bacterial cell) envelope: Mechanisms and inhibitors of outer membrane biogenesis

Thiago Santos, PhD
Department of Chemistry and Chemical Biology
Northeastern University

Transmembrane β-barrel proteins are integral components of the outer membrane (OM) of Gram-negative bacteria; they are essential for establishing the impermeability of the bacterial cell envelope to toxic molecules such as antibiotics. Assembly of β-barrels is facilitated by the β-barrel assembly machine (BAM), a multiprotein complex conserved across all Gram-negative organisms. Despite extensive understanding of the structure and function of BAM, the mechanistic details underlying BAM-mediated folding and membrane integration of structurally diverse β-barrel substrates remain largely unknown. Our group investigates this process by characterizing folding intermediates in vivo and by studying the mode of action of natural products that target BAM. This approach provides insight into the physiology of the bacterial cell envelope and informs the design of mechanism-based inhibitors of OM biogenesis. In this seminar, I will discuss how we probe substrate folding in vivo, and present recent findings that clarify the catalytic process.
 

Department Seminar