Chemistry Colloquium Program

Jason P. LeJeune, Ph.D.

Safety Seminar

Host: John A. Pojman

Amy Xu, Ph.D. 

"From Phase Separation to Vaccine Design: Small-Angle Scattering in Biomolecular Research"

Small-Angle Scattering (SAS), including Small-Angle X-ray and Neutron Scattering (SAXS and SANS), is a powerful characterization technique for investigating the structure and dynamics of biomacromolecules, as well as their interactions. SAXS/SANS enables the characterization of structural features across a wide range of length scales, from just a few nanometers to several hundred nanometers. Additionally, SANS offers unique advantages through contrast matching, allowing for the selective characterization of individual components within complex structures and providing insights into the hydration states of the measured materials. Our research group utilizes SAXS/SANS to investigate biomacromolecular interactions with the primary objective of gaining a deeper understanding of their biological functions and material properties. Our research extends in two major directions: (1) Understanding the phase behavior of biomacromolecular complexes in various crowded environments, as recent studies indicate that liquid-liquid phase separation of biomacromolecules underlies the formation of diverse biological structures, ranging from membraneless organelles to pollen grains, and (2) Elucidating the mechanism of action of aluminum adjuvants in vaccine formulations. By employing SAXS and SANS, we have probed the hydration and porosity of aluminum adjuvants, providing critical insights into their microstructures. These findings offer a fresh perspective on the mechanism of action of aluminum adjuvants, addressing a long-standing mystery in vaccine research. In this presentation, I will demonstrate how we leverage SAXS and SANS to achieve these research objectives. 

Host: Donghui Zhang

Zakiya Wilson-Kennedy, Ph.D.

Hosts: Graca Vicente & John Pojman 

 

Fatima Rivas, Ph.D. 

"The Next Generation of Therapeutic Agents Based on Natural Products: From Fundamental Research to Clinical Applications"

Natural compound-derived medicines are experiencing a renaissance, as modern scientific techniques unlock their potential for addressing life-threatening diseases. This evolution bridges ethnopharmacology with cutting-edge drug development methodologies, creating innovative therapeutic solutions that combine the wisdom of traditional medicine with the precision of contemporary pharmaceutical science. The Rivas group seeks to identify and harness the potential of molecular editing in order to establish structure to function relationships. This seminar will explore fundamental techniques for creating carbon-carbon bonds that facilitate the development of novel natural product mimetics.

Cycloaddition reactions offer exceptional atomic efficiency while constructing complex molecular structures. The Rivas laboratory initiated two major research projects based on these reactions: a) synthesis of quinoline/isoquinoline-based alkaloid natural product-like structures designed to cross the blood-brain barrier. Our compounds demonstrate promising anticancer activity in diffuse intrinsic pontine glioma (DIPG) models and also display fluorescent characteristics. b) synthesis of steroidal natural products using cycloaddition reactions to generate multigram quantity in order to advance them to in vivo model studies. Our medicinal chemistry campaigns address major concerns associated with i) poor water solubility, which complicates drug delivery and bioavailability, ii) metabolic instability, often leading to rapid clearance or conversion to unwanted metabolites, and iii) off-target effects, producing side effects.

Our endeavors have provided lead compounds that demonstrate in vivo model efficacy against solid tumor, while displaying no acute toxicity in murine models.

Hosts: Graca Vicente & John Pojman

Benjamin P. Boussert Lectureship

Christine M. Micheel, Ph.D.

"Uses of Generative AI in Cancer Research and Clinical Care"

Hosts: Graca Vicente & John Pojman

Ayyalusamy (Rams) Ramamoorthy, Ph.D.

“Probing Membrane-Assisted Protein-Protein Interactions by NMR”

Molecular interactions at the cell membrane interface play vital roles on the pathomechanisms of various diseases including infection and aging related diseases. Therefore, high-resolution investigation of membrane-associated molecular events would be useful for biomedical applications. However, despite the recent developments in structural biology, probing dynamic protein-protein and protein-membrane interactions continues to pose tremendous challenges to most biophysical techniques. A major area of research in my group has been focused on the development of approaches to study the dynamic structural interactions between membrane bound proteins that are implicated in the pathology of many diseases. My lecture will focus on the approaches developed to overcome the major challenges related two such examples.  

Our research has contributed towards the development of membrane mimetics (such as nanodiscs and bicelles) and NMR approaches to study the dynamic structural interactions between membrane bound proteins such as cytochromes (~16-kDa b5, ~57-kDa P450, ~80-kDa P450-reductase).^1,2 Strategies to study the dynamic structures of these challenging systems and electron transfer mechanism related to cytochrome-P450’s enzymatic function will be presented in the first half of my talk.^3,4 The development and applications of a variety of polymer-based nanodiscs will also be highlighted.

My research group has also been investigating the self-assembly process related to protein aggregation and phase separation.^5-9 In the second-half of my presentation, structures of early intermediates of amyloid peptides, mechanisms of amyloid-induced membrane disruption, and amyloid inhibition by small molecule compounds will be discussed. Particularly, our recent studies on the membrane interaction and cell toxicity of amyloid-beta, implicated in Alzheimer’s Disease, and islet amyloid polypeptide (IAPP, or also known as amylin), implicated in Type-2 diabetes, will be discussed. 

 

References:

1. Dürr et al., Chem. Rev. 112 (2012) 6054-6074.
2. Dürr et al., BBA Biomembranes 1768 (2007) 3235-3259.
3. Barnaba et al., Chem. Phys. Chem. 19 (2018) 2603-2613.
4. Ravula et al., Angew. Chem. 56 (2021) 16885-16888.
5. Brender et al., Acc. Chem. Res. 45 (2012) 454-462.
6. Kotler et al., Chem. Soc. Rev. 43 (2014) 6692-6700.
7. Milardi et al Chem. Rev. 121 (2021) 1845-1893.
8. Ivanova et al Biophys. Chem. 269 (2021) 106507.
9. Nguyen et al Chem. Rev. 121 (2021) 2545-2647. 

Host: Pu Duan

Nathaniel Gilbert, Ph.D. 

"Gatekeeping the Iron: How the Polypeptide Regulates Catalysis in Animal Lipoxygenases" 

Understanding proteins in their native environments and the full conformational landscapes they explore is essential for linking structure to function. This seminar focuses on lipoxygenases (LOXs), a family of non-heme, primarily iron-containing enzymes that catalyze the regio- and stereospecific oxygenation of polyunsaturated fatty acids (PUFAs) released from membranes by phospholipases. While phospholipases rely on membrane interfaces for activation, certain LOXs exhibit a remarkable duality: they remain active in soluble systems but demonstrate accelerated catalysis at lipid-water interfaces. This presentation will delve into the molecular basis of this "interfacial acceleration" across the LOX phylogeny, a critical knowledge gap in the field. By integrating evolutionary biochemistry, AI-driven structural predictions, advanced biophysical techniques, and crystal/cryo-EM structures, this work uncovers conserved mechanisms of LOX activation. Ultimately, the findings provide new insights into motion-based drug design targeting key human lipoxygenases.

 

Host: Gerald Schneider

Michele Smith

Rebecca Chiasson, M.S. 

Mihaela C. Stefan, Ph.D.

"Amphiphilic Polycaprolactone Diblock Copolymers for Drug Delivery of Anticancer Drugs"

Amphiphilic polycaprolactone (PCL) diblock copolymers are synthesized by the ring-opening polymerization of various g-substituted ε-caprolactone monomers and self-assembled into the water to form micelles, which can improve the loading of anticancer drugs. The drug-loaded micelles can passively target tumors through an enhanced permeability and retention (EPR) effect. Our research has focused on:

(i) Strategies to increase the drug loading capacity of the amphiphilic diblock copolymer micelles by tuning substituents at the hydrophobic block and/or co-loading with polyphenols, such as resveratrol and quercetin. Non-covalent interactions, such as pi-stacking and hydrogen bonding between the anticancer drug, doxorubicin, and polyphenol, have increased drug loading capacity;

(ii) High glutathione production is one of the defense mechanisms cancer cells develop to survive elevated oxidative stress and resist certain anticancer drugs. Specifically, depleting glutathione with doxorubicin-loaded micelle prepared from a novel 2,3-diiodomaleimide-functionalized PCL exhibited significant cancer cell death;

(iii) Enediyne-maleimide substituent generates diradical upon their activation cleaves DNA in cancer cells leading to cytotoxicity as inspired by calicheamicin; 

(iv) a microfluidic device to cultivate stem cell-derived organoids to simulate the dynamic microenvironment of the organ and test the toxicity of drug-loaded micelles. The cell-cell and cell-matrix interactions found in living organs can improve the evaluation of ex vivo toxicity of drug-loaded micelles.

 

Host: David Spivak

Julie Albert, Ph.D. 

Host: Gerald Schneider