Medicinal-Pharmaceutical Chemistry Commons^™

Allosteric Control Overcomes Steric Limitations For Neutralizing Antibodies Targeting Conserved Binding Epitopes Of The Sars-Cov-2 Spike Protein: Exploring The Intersection Of Binding, Allostery, And Immune Escape With A Multimodal Computational Approach, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate …

Dynamic Mutational Profiling Of Binding Interactions And Allosteric Networks In Conformational Ensembles Of The Sars-Cov-2 Spike Protein Complexes With Classes Of Antibodies Targeting Cryptic Binding Sites: Confluence Of Binding And Allostery Determines Molecular Mechanisms And Hotspots Of Immune Escape, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The ongoing evolution of SARS-CoV-2 variants has underscored the need to understand not only the structural basis of antibody recognition but also the dynamic and allosteric mechanisms that could underlie complexity of broad and escape-resistant neutralization. In this study, we employed a multi-scale approach integrating structural analysis, hierarchical molecular simulations, mutational scanning and network-based allosteric modeling to dissect how Class 4 antibodies (represented by S2X35, 25F9, and SA55) and Class 5 antibodies (represented by S2H97, WRAIR-2063 and WRAIR-2134) can modulate conformational behavior, binding energetics, allosteric interactions and immune escape patterns of the SARS-CoV-2 spike protein. Using hierarchical simulations of the …

Mutational Scanning And Binding Free Energy Computations Of The Sars-Cov-2 Spike Complexes With Distinct Groups Of Neutralizing Antibodies: Energetic Drivers Of Convergent Evolution Of Binding Affinity And Immune Escape Hotspots, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Nishank Raisinghani, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The rapid evolution of SARS-CoV-2 has led to the emergence of variants with increased immune evasion capabilities, posing significant challenges to antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural and energetic analysis of SARS-CoV-2 spike receptor-binding domain (RBD) complexes with neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, group B AZD8895 and REGN10933, group C LY-CoV555, and group D antibodies AZD1061, REGN10987, and LY-CoV1404. Using coarse-grained simplified simulation models, rapid energy-based mutational scanning, and rigorous MM-GBSA binding free energy calculations, we elucidated the molecular mechanisms of antibody binding and escape mechanisms, identified key …

Quantitative Characterization And Prediction Of The Binding Determinants And Immune Escape Hotspots For Groups Of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling Of The Sars-Cov-2 Spike Complexes With Antibodies, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Nishank Raisinghani, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by the balance and tradeoff between multiple energetic factors and interaction contributions of the evolving escape hotspots involved in antigenic drift and convergent evolution. However, the dynamic and energetic details quantifying the balance and contribution of these factors, particularly the balancing nature of specific interactions formed by antibodies with epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning of SARS-CoV-2 spike residues, and binding free energy computations for two distinct groups …

Asymmetric Synthesis Of The Hiv Protease Inhibitor Tmc-126 And An Anti-Malarial Agent Via A Titanium Tetrachloride Mediated Asymmetric Glycolate Aldol Addition Reaction. Redefining The Curtius Rearrangement Reaction Via Dehomologation Of Carboxylic Acids Bearing Alpha-Leaving Groups, Kweku Amaning Affram

Theses and Dissertations

Acquired Immune Deficiency Syndrome (AIDS) and malaria are two devastating infectious diseases caused by HIV and Plasmodium parasites. AIDS is caused by HIV-1 and HIV-2, transmitted through sexual contact, blood transfusions, needle sharing, and perinatal routes. Malaria, caused by plasmodium parasites through mosquito bites. Today, millions of people around the world have been infected with HIV and malaria and much research has been done to treat it. However, despite advancements in therapeutic options, these diseases remain a significant global health threat, particularly in developing countries due to the emergence of drug-resistant strains for both HIV and malaria complicating eradication efforts. …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Rwanda's Natural Remedies: A Fresh Look At The Fight Against Malaria, Leandre Nsabimana Ndisanze

Pomona Senior Theses

Malaria remains one of the most devastating parasitic diseases globally, disproportionately affecting sub-Saharan Africa, where Rwanda continues to face high transmission rates and rising resistance to conventional interventions. Despite decades of control efforts, the emergence of drug-resistant Plasmodium falciparum and insecticide-resistant Anopheles mosquitoes threatens to reverse recent gains. This research responds to the urgent need for sustainable and culturally relevant alternatives by exploring the therapeutic potential of Rwandan traditional medicinal plants. These indigenous remedies, long used by local healers, offer an underexplored reservoir of bioactive compounds that may provide the basis for novel antimalarial drugs.

The central hypothesis of this …

Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

Rings Of Power: Controlling Sod Mimic Activity By The Addition Of Pyridine Rings Within The Pyridinophane Scaffold, Katherine J. Smith, Timothy M. Schwartz, David M. Freire, Cameron Bowers, Sarah K. Dunn, Jackson F. Bonnell, Magy A. Mekhail, Giridhar Akkaraju, Kayla N. Green

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Superoxide dismutase enzymes are a major defense against superoxide, which is a potent reactive oxygen species. Misregulation of reactive oxygen species and subsequent neuronal damage are etiological hallmarks of neurodegenerative disease. Macrocyclic small molecules have offered inroads toward functional SOD1 mimics. Herein, we report a series of five tetra-aza macrocyclic ^RPy₂N₂ ligands, varied by 4-position substitution of the pyridine ring with both electron-donating (R = OMe) and withdrawing groups (R = Cl, I, and CF₃) to offer the first comparison to well-studied ^RPyN₃ congeners and other mimics in the literature. New ligands …

Alphafold2 Modeling And Molecular Dynamics Simulations Of The Conformational Ensembles For The Sars-Cov-2 Spike Omicron Jn.1, Kp.2 And Kp.3 Variants: Mutational Profiling Of Binding Energetics Reveals Epistatic Drivers Of The Ace2 Affinity And Escape Hotspots Of Antibody Resistance, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

AlphaFold2-based atomistic predictions of structures and conformational ensembles of the SARS-CoV-2 spike complexes with the host receptor ACE2 for the most dominant Omicron variants JN.1, KP.1, KP.2 and KP.3 to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and computations of binding affinities, we identified binding energy hotspots and characterized the molecular basis underlying epistatic couplings between convergent mutational hotspots. The results suggested the existence of epistatic interactions between convergent mutational sites at L455, F456, Q493 positions that protect and restore …

A New Approach For Discriminating Spatially Acquired Sers Spectra Using Antiretroviral Drug Emtricitabine As A Test Sample, Jana Hrncirova, Marguerite R. Butler, Meredith R. Clark, Gustavo F. Doncel, John B. Cooper

Chemistry & Biochemistry Faculty Publications

In this study, an antiretroviral drug emtricitabine (also known as FTC or Emtriva) was detected and quantified down to 40 ng/ml by using surface-enhanced Raman spectroscopy (SERS). Its aqueous standards were tested with two types of silver nanoparticles (colloidal and dendritic) using a specially developed aluminum well plate. The SERS spectra were acquired using a Raman scanning device with 30-mu m spatial resolution. The spectral data were analyzed using a new approach for the discrimination of the spatially acquired spectra based on the Quality index (Qi). After the Qi is calculated, the spectral data are sorted based on the Qi. …

Additive Effects Of Cyclic Peptide [R4w4] When Added Alongside Azithromycin And Rifampicin Against Mycobacterium Avium Infection, Melissa Kelley, Kayvan Sasaninia, Arbi Abnousian, Ali Badaoui, James Owens, Abrianna Beever, Nala Kachour, Rakesh Kumar Tiwari, Vishwanath Venketaraman

Pharmacy Faculty Articles and Research

Mycobacterium avium (M. avium), a type of nontuberculous mycobacteria (NTM), poses a risk for pulmonary infections and disseminated infections in immunocompromised individuals. Conventional treatment consists of a 12-month regimen of the first-line antibiotics rifampicin and azithromycin. However, the treatment duration and low antibiotic tolerability present challenges in the treatment of M. avium infection. Furthermore, the emergence of multidrug-resistant mycobacterium strains prompts a need for novel treatments against M. avium infection. This study aims to test the efficacy of a novel antimicrobial peptide, cyclic [R4W4], alongside the first-line antibiotics azithromycin and rifampicin in reducing M. avium survival. Colony-forming unit (CFU) …

Probing Conformational Landscapes Of Binding And Allostery In The Sars-Cov-2 Omicron Variant Complexes Using Microsecond Atomistic Simulations And Perturbation-Based Profiling Approaches: Hidden Role Of Omicron Mutations As Modulators Of Allosteric Signaling And Epistatic Relationships, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we systematically examine the conformational dynamics, binding and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 spike protein complexes with the ACE2 host receptor using molecular dynamics simulations and perturbation-based network profiling approaches. Microsecond atomistic simulations provided a detailed characterization of the conformational landscapes and revealed the increased thermodynamic stabilization of the BA.2 variant which can be contrasted with the BA.4/BA.5 variants inducing a significant mobility of the complexes. Using the dynamics-based mutational scanning of spike residues, we identified structural stability and binding affinity hotspots in the Omicron complexes. Perturbation response scanning and network-based mutational …

Balancing Functional Tradeoffs Between Protein Stability And Ace2 Binding In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic And Energetic Changes, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and …

Coarse-Grained Molecular Simulations And Ensemble-Based Mutational Profiling Of Protein Stability In The Different Functional Forms Of The Sars-Cov-2 Spike Trimers: Balancing Stability And Adaptability In Ba.1, Ba.2 And Ba.2.75 Variants, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies have suggested that the emergence of Omicron variants can be determined by multiple fitness tradeoffs including immune escape, binding affinity, conformational plasticity, protein stability, and allosteric modulation. In this study, we embarked on a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the different functional states of spike trimers for BA.1, BA.2, and BA.2.75 variants. Using efficient and accurate coarse-grained simulations and atomistic reconstruction of the ensembles, we examined the conformational dynamics of the spike trimers that agree with the recent functional studies, suggesting that BA.2.75 trimers are the most stable …

Virtual And In Vitro Screening Of Natural Products Identifies Indole And Benzene Derivatives As Inhibitors Of Sars-Cov-2 Main Protease (MPro), Dony Ang, Riley Kendall, Hagop S. Atamian

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The rapid spread of the coronavirus disease 2019 (COVID-19) resulted in serious health, social, and economic consequences. While the development of effective vaccines substantially reduced the severity of symptoms and the associated deaths, we still urgently need effective drugs to further reduce the number of casualties associated with SARS-CoV-2 infections. Machine learning methods both improved and sped up all the different stages of the drug discovery processes by performing complex analyses with enormous datasets. Natural products (NPs) have been used for treating diseases and infections for thousands of years and represent a valuable resource for drug discovery when combined with …

Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses

Drug metabolism is the biochemical process of modifying drugs to detoxify and remove them through enzymatic transformations. These biotransformation’s occur primarily in the liver and are critical to understanding how pharmaceutical compounds are chemically altered inside the human body. Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19, remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including …

A Macrocyclic Molecule With Multiple Antioxidative Activities Protects The Lens From Oxidative Damage, Jinmin Zhang, Yu Yu, Magy A. Mekhail, Hongli Wu, Kayla N. Green

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Growing evidence links oxidative stress to the development of a cataract and other diseases of the eye. Treatments for lens-derived diseases are still elusive outside of the standard surgical interventions, which still carry risks today. Therefore, a potential drug molecule ^OHPy₂N₂ was explored for the ability to target multiple components of oxidative stress in the lens to prevent cataract formation. Several pathways were identified. Here we show that the ^OHPy₂N₂ molecule activates innate catalytic mechanisms in primary lens epithelial cells to prevent damage induced by oxidative stress. This protection was linked to …

Probing Mechanisms Of Binding And Allostery In The Sars-Cov-2 Spike Omicron Variant Complexes With The Host Receptor: Revealing Functional Roles Of The Binding Hotspots In Mediating Epistatic Effects And Communication With Allosteric Pockets, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we performed all-atom MD simulations of RBD–ACE2 complexes for BA.1, BA.1.1, BA.2, and BA.3 Omicron subvariants, conducted a systematic mutational scanning of the RBD–ACE2 binding interfaces and analysis of electrostatic effects. The binding free energy computations of the Omicron RBD–ACE2 complexes and comprehensive examination of the electrostatic interactions quantify the driving forces of binding and provide new insights into energetic mechanisms underlying evolutionary differences between Omicron variants. A systematic mutational scanning of the RBD residues determines the protein stability centers and binding energy hotpots in the Omicron RBD–ACE2 complexes. By employing the ensemble-based global network analysis, we …

Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

n this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the …

Biophysical Insight Into The Sars-Cov2 Spike–Ace2 Interaction And Its Modulation By Hepcidin Through A Multifaceted Computational Approach, Hamid Hadi-Alijanvand, Luisa Di Paola, Guang Hu, David M. Leitner, Gennady M. Verkhivker, Peixin Sun, Humanath Poudel, Alessandro Giuliani

Mathematics, Physics, and Computer Science Faculty Articles and Research

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection …

Computer Simulations And Network-Based Profiling Of Binding And Allosteric Interactions Of Sars-Cov-2 Spike Variant Complexes And The Host Receptor: Dissecting The Mechanistic Effects Of The Delta And Omicron Mutations, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we combine all-atom MD simulations and comprehensive mutational scanning of S-RBD complexes with the angiotensin-converting enzyme 2 (ACE2) host receptor in the native form as well as the S-RBD Delta and Omicron variants to (a) examine the differences in the dynamic signatures of the S-RBD complexes and (b) identify the critical binding hotspots and sensitivity of the mutational positions. We also examined the differences in allosteric interactions and communications in the S-RBD complexes for the Delta and Omicron variants. Through the perturbation-based scanning of the allosteric propensities of the SARS-CoV-2 S-RBD residues and dynamics-based network centrality and …

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …

The Temperature-Dependent Conformational Ensemble Of Sars-Cov-2 Main Protease (Mpro), Ali Ebrahim, Blake T. Riley, Desigan Kumaran, Babak Andi, Martin R. Fuchs, Sean Mcsweeney, Daniel A. Keedy

Publications and Research

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M^pro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M^pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M^pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M^pro, including …

Atomistic Simulations And In Silico Mutational Profiling Of Protein Stability And Binding In The Sars-Cov-2 Spike Protein Complexes With Nanobodies: Molecular Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structure-functional studies have recently revealed a spectrum of diverse high-affinity nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this study, we combine atomistic simulations with the ensemble-based mutational profiling of binding for the SARS-CoV-2 S-RBD complexes with a wide range of nanobodies to identify dynamic and binding affinity fingerprints and characterize the energetic determinants of nanobody-escaping mutations. Using an in silico mutational profiling approach for probing the protein stability and binding, we examine dynamics and energetics of the SARS-CoV-2 complexes with single nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E + …

Ganglioside Alters Phospholipase Trafficking, Inhibits Nf-Κb Assembly, And Protects Tight Junction Integrity, John J. Miklavcic, Qun Li, Jordan Skolnick, Alan B. R. Thomson, Vera C. Mazurak, Michael Tom Clandinin

Food Science Faculty Articles and Research

Background and Aims: Dietary gangliosides are present in human milk and consumed in low amounts from organ meats. Clinical and animal studies indicate that dietary gangliosides attenuate signaling processes that are a hallmark of inflammatory bowel disease (IBD). Gangliosides decrease pro-inflammatory markers, improve intestinal permeability, and reduce symptoms characteristic in patients with IBD. The objective of this study was to examine mechanisms by which dietary gangliosides exert beneficial effects on intestinal health.

Methods: Studies were conducted in vitro using CaCo-2 intestinal epithelial cells. Gangliosides were extracted from milk powder and incubated with differentiated CaCo-2 cells after exposure to pro-inflammatory stimuli. …

The Mechanism Of Β-N-Methylamino-L-Alanine Inhibition Of Trna Aminoacylation And Its Impact On Misincorporation, Nien-Ching Han, Tammy J. Bullwinkle, Kaeli F. Loeb, Kym F. Faull, Kyle Mohler, Jesse Rinehart, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

β-N-methylamino-l-alanine (BMAA) is a nonproteinogenic amino acid that has been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). BMAA has been found in human protein extracts; however, the mechanism by which it enters the proteome is still unclear. It has been suggested that BMAA is misincorporated at serine codons during protein synthesis, but direct evidence of its cotranslational incorporation is currently lacking. Here, using LC-MS–purified BMAA and several biochemical assays, we sought to determine whether any aminoacyl-tRNA synthetase (aaRS) utilizes BMAA as a substrate for aminoacylation. Despite BMAA's previously predicted misincorporation at serine …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Applied Molecular Dynamics: From Targeting Viral Helicases, To Understanding The Interactions Of Cucurbituril Complexes In Ionic Solutions, Bryan Raubenolt

LSU New Orleans Theses and Dissertations

Molecular Dynamics simulations are a highly useful tool in helping understand the fundamental interactions present in a variety of chemical systems. The work discussed here illustrates it’s use in determining the conformational dynamics of the Zika and SARS-Cov-2 helicase in a physiological environment, largely in an effort to discover inhibitors capable of rendering the protein inert. Additionally, we show how it can be used to understand paradoxical trends in the anion-induced precipitation of Cucurbituril cavitands.

Viral helicases are motor proteins tasked with unwinding the viral dsRNA, a crucial step in preparing the strand to be translatable by host cells. By …

Nuclear-Targeted Gold Nanoparticles Enhance The Effects Of Radiation Therapy With And Without Liposomal Delivery, Maureen Aliru

Dissertations and Theses (Open Access)

Less that 10% of pancreatic cancer patients are eligible for curative resection, and clinical trials evaluating chemoradiation in locally advanced patients with unresectable disease have been largely disappointing. New and creative therapeutic approaches are needed to address the unment need for treatment options. The objective of this thesis is to advance radiosensitization of treatment-resistant densely desmoplastic pancreatic cancer using nanoparticles to surmount biological barriers to effective particle distribution for DNA-targeting.

Clinical translation of radiosensitizing nanoparticles has stalled owing to technical challenges. Current strategies to use AuNPs for radiosensitization require large quantities of gold, kilovoltage x-rays, immediate irradiation after intravenous administration, …