Donnan Potential Across The Outer Membrane Of Gram-Negative Bacteria And Its Effect On The Permeability Of Antibiotics, Olaniyi Alegun, Ankit Pandeya, Jian Cui, Isoiza Ojo, Yinan Wei
Chemistry Faculty Publications
The cell envelope structure of Gram-negative bacteria is unique, composed of two lipid bilayer membranes and an aqueous periplasmic space sandwiched in between. The outer membrane constitutes an extra barrier to limit the exchange of molecules between the cells and the exterior environment. Donnan potential is a membrane potential across the outer membrane, resulted from the selective permeability of the membrane, which plays a pivotal role in the permeability of many antibiotics. In this review, we discussed factors that affect the intensity of the Donnan potential, including the osmotic strength and pH of the external media, the osmoregulated periplasmic glucans ...
Synthetic And Biological Studies On Benzazepine Derivatives As Dopamine Receptor Ligands, 2021 The Graduate Center, City University of New York
Synthetic And Biological Studies On Benzazepine Derivatives As Dopamine Receptor Ligands, Rajan Giri
Dissertations, Theses, and Capstone Projects
Dopamine (DA) receptors, members of the G-protein coupled receptors (GPCRs) family, are divided in two groups based on their transmembrane structural homology domains: D1R-like (D1R, D5R sub-types) and D2R-like DA receptors (D2R, D3R and D4R sub-types). Disturbances in dopaminergic neurotransmission are associated with several CNS disorders. Hence, DA receptor selective ligands have been sought as pharmacological agents to normalize perturbations in the dopaminergic system. Despite several notable efforts, the discovery of highly selective ligands for dopamine receptor sub-types has proved challenging due to close transmembrane structural similarity, especially between DA receptor sub-types within the same group.
The 1-phenylbenzazepine scaffold is ...
Theranostic Applications Of Sirna Bioconjugates In Cancer Detection And Treatment, 2021 Seton Hall University
Theranostic Applications Of Sirna Bioconjugates In Cancer Detection And Treatment, Sunil S. Shah
Seton Hall University Dissertations and Theses (ETDs)
The emerging field of RNA nanotechnology has led to rapid advances in the applications of RNA in chemical biology, medicinal chemistry, and biotechnology. At the forefront of its utility is the ability to self-assemble multiple siRNAs into nanostructure formulations capable of targeting selected oncogenes and potentiating the gene therapy of malignant tumors. Self-assembled siRNA integrates multiple siRNAs within a single molecular platform for silencing multiple oncogenic mRNA targets with high precision and efficacy to potentially induce cancer cell apoptosis through the RNA interference (RNAi) pathway. Furthermore, the conjugation of siRNA self-assemblies with bio-active probes results in multi-functional theranostic (therapy ...
Structure Elucidation Of The Elusive Enzyme I Monomer Reveals The Molecular Mechanisms Linking Oligomerization And Enzymatic Activity, Trang T. Nguyen, Rodolfo Ghirlando, Julien F. Roche, Vincenzo Venditti
Enzyme I (EI) is a phosphotransferase enzyme responsible for converting phosphoenolpyruvate (PEP) into pyruvate. This reaction initiates a five-step phosphorylation cascade in the bacterial phosphotransferase (PTS) transduction pathway. Under physiological conditions, EI exists in an equilibrium between a functional dimer and an inactive monomer. The monomer–dimer equilibrium is a crucial factor regulating EI activity and the phosphorylation state of the overall PTS. Experimental studies of EI’s monomeric state have yet been hampered by the dimer’s high thermodynamic stability, which prevents its characterization by standard structural techniques. In this study, we modified the dimerization domain of EI (EIC ...
Theranostic Nanoparticles Folic Acid-Carbon Dots-Drug(S) For Cancer, 2021 East Tennessee State University
Theranostic Nanoparticles Folic Acid-Carbon Dots-Drug(S) For Cancer, Godwin Kweku Babanyinah
Electronic Theses and Dissertations
This study aims to prepare theranostic nanoparticles (NPs) that are expected to increase cancer diagnostics and therapeutic efficacy. We prepared the NPs constituting carbon dots (CDs) as an imaging agent, folic acid as a targeting agent, doxorubicin (DOX), or gemcitabine (GEM) as chemotherapy agents. The NPs include noncovalent FA-CDs-DOX, covalent CDs-FA-DOX, and covalent FA-CDs-GEM. Through ultraviolet-visible spectroscopy, fluorescence spectroscopy, and Fourier transform-infrared spectroscopy, the fabrication of these NPs was confirmed. It was discovered that the high drug loading efficiency is the noncovalent series while the high drug loading capacity is the covalent series The in-vitro pH-dependent drug release data indicate ...
Sulfur Anions: Comments Upon Structure, 2021 University of Nebraska-Lincoln
Sulfur Anions: Comments Upon Structure, Charles A. Kingsbury
Faculty Publications -- Chemistry Department
This work emphasizes the need for solvent simulation as well as a counterion in calculations concerning anions, although optimization may be difficult. Solvent and counterion both play a large role in conformation of the ion. Part of the reason for the success of sulfur anions in chemical reactions may be the ability of sulfone oxygen(s) to coordinate with the counterion (usually lithium). The “solvent” partially dissociates lithium from the carbanion center.
Using Molecular Dynamics Simulations To Understand Receptor-Complex Communication And Signaling, Hannah Margaret Hoag
Theses and Dissertations
The overarching purpose of this document is to use Computer-aided drug design and Molecular dynamic simulations to better understand elusive drug-receptor interactions, as well as various types of inter-receptor signaling. Chapter One introduces the theory and importance of Computer-aided drug design and the methodology used in both Chapters Two and Three.
Chapter Two uncovers the relationship between the well-studied ABCB1 transporter and a newly identified drug known as Xanthohumol (XN). XN is compared to a commonly used drug, Doxorubicin (DOX), in this chapter. If the ABCB1 transporter can be properly inhibited, cancer-fighting drugs will be able to stay within the ...
Label‑Free Spectral Imaging To Study Drug Distribution And Metabolism In Single Living Cells, 2021 Chapman University
Label‑Free Spectral Imaging To Study Drug Distribution And Metabolism In Single Living Cells, Qamar Alshammari, Rajasekharreddy Pala, Nir Katzir, Surya M. Nauli
Pharmacy Faculty Articles and Research
During drug development, evaluation of drug and its metabolite is an essential process to understand drug activity, stability, toxicity and distribution. Liquid chromatography (LC) coupled with mass spectrometry (MS) has become the standard analytical tool for screening and identifying drug metabolites. Unlike LC/MS approach requiring liquifying the biological samples, we showed that spectral imaging (or spectral microscopy) could provide high-resolution images of doxorubicin (dox) and its metabolite doxorubicinol (dox’ol) in single living cells. Using this new method, we performed measurements without destroying the biological samples. We calculated the rate constant of dox translocating from extracellular moiety into the ...
The Mechanism Of Β-N-Methylamino-L-Alanine Inhibition Of Trna Aminoacylation And Its Impact On Misincorporation, 2021 The Ohio State University
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 ...
Nad(H) Phosphates Mediate Tetramer Assembly Of Human C-Terminal Binding Protein (Ctbp), 2021 University of Massachusetts Medical School
Nad(H) Phosphates Mediate Tetramer Assembly Of Human C-Terminal Binding Protein (Ctbp), Jeffry C. Nichols, Celia A. Schiffer, William E. Royer
University of Massachusetts Medical School Faculty Publications
C-terminal binding proteins (CtBPs) are co-transcriptional factors that play key roles in cell fate. We have previously shown that NAD(H) promotes the assembly of similar tetramers from either human CtBP1 and CtBP2 and that CtBP2 tetramer destabilizing mutants are defective for oncogenic activity. To assist structure-based design efforts for compounds that disrupt CtBP tetramerization, it is essential to understand how NAD(H) triggers tetramer assembly. Here, we investigate the moieties within NAD(H) that are responsible for triggering tetramer formation. Using multi-angle light scattering (MALS) we show that ADP is able to promote tetramer formation of both CtBP1 and ...
Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, 2021 Dana-Farber Cancer Institute
Unique Structural Solution From A Vh3-30 Antibody Targeting The Hemagglutinin Stem Of Influenza A Viruses, Wayne D. Harshbarger, Derrick Deming, Gordon J. Lockbaum, Nattapol Attatippaholkun, Maliwan Kamkaew, Shurong Hou, Mohan Somasundaran, Jennifer P. Wang, Robert W. Finberg, Quan Karen Zhu, Celia A. Schiffer, Wayne A Marasco
Schiffer Lab Publications
Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined ...
Crystal Structure Of Sars-Cov-2 Main Protease In Complex With The Non-Covalent Inhibitor Ml188, 2021 University of Massachusetts Medical School
Crystal Structure Of Sars-Cov-2 Main Protease In Complex With The Non-Covalent Inhibitor Ml188, Gordon J. Lockbaum, Archie C. Reyes, Jeong Min Lee, Ronak Tilvawala, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Paul R. Thompson, Celia A. Schiffer
COVID-19 Publications by UMMS Authors
Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M(pro)) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M(pro), and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M(pro) at 2.5 microM, which is ...
Synthesis And Cytotoxicity Of Trisubstituted Imidazoles, 2021 Rowan University
Synthesis And Cytotoxicity Of Trisubstituted Imidazoles, Venkata Agasthya Kasibotla
Theses and Dissertations
Aza heterocyclic compounds are an important class of organic compounds that play a major role in medicinal chemistry. Majority of the heterocyclic motifs such as imidazoles, triazoles, piperazines etc. act as building blocks for synthesizing active pharmaceutical ingredients. Several pharmaceutical drugs include these motifs due to their varying physicochemical properties, which enable them to exhibit wide range of pharmacological activities ranging from anti-fungal, anti-neoplastic, anti-helmintic, anti-microbial etc. Owing to their electron rich ring system, imidazole and piperazine based motifs have become an attractive target for design and development of novel chemical structures as new drugs. In the current study, we ...
Two-Way Regulation Of Mmpl3 Expression Identifies And Validates Inhibitors Of Mmpl3 Function In Mycobacterium Tuberculosis, Shipra Grover, Curtis A. Engelhart, Esther Perez-Herran, Wei Li, Katherine A. Abrahams, Kadamba Papavinasasundaram, James M. Bean, Christopher M. Sassetti, Alfonso Mendoza-Losana, Gurdyal S. Besra, Mary Jackson, Dirk Schnappinger
Open Access Publications by UMMS Authors
MmpL3, an essential mycolate transporter in the inner membrane of Mycobacterium tuberculosis (Mtb), has been identified as a target of multiple, chemically diverse antitubercular drugs. However, several of these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe a cell-based assay that utilizes two-way regulation of MmpL3 expression to readily identify MmpL3-specific inhibitors. We successfully used this assay to identify a novel guanidine-based MmpL3 inhibitor from a library of 220 compounds that inhibit growth of Mtb by largely unknown mechanisms. We furthermore identified inhibitors of cytochrome bc1-aa3 oxidase as one class ...
Synthesis Of Dual Small Molecule Hybrids To Probe The Synergy Between Dna Repair Enzymes And Ido1, 2021 University of Kentucky
Synthesis Of Dual Small Molecule Hybrids To Probe The Synergy Between Dna Repair Enzymes And Ido1, Nathaniel George
Theses and Dissertations--Chemistry
Indoleamine 2 3-dioxygenase (IDO) has recently been highlighted as a promising target for small molecule based immunotherapy. IDO is often coopted by various cancer cells to promote an immune-suppressive environment around tumors. DNA damage repair (DDR) enzymes have recently been targeted for inhibition to promote genetic instability and bolster immune recognition. DDR enzymes such as PARP and POLγ are common inhibition targets due to their direct effects on cellular function. In the process of designing conjugate inhibitors of IDO and DDR enzymes, novel synthetic methodology was developed for the mild deprotection of N-Tert-butyloxycarbonyl (N-BOC) group from various amines. Conjugate ...
Using Nmr Spectroscopy And Computational Chemistry To Confirm The Structure Of Novel Antibiotic Nocamycin O, Stephanie Lewis
CMC Senior Theses
In recent years, many medically promising antibiotics have been discovered in nature, especially in insect-microbe symbioses. One of the better-studied examples of this kind of defensive relationship is that of fungus-growing ants and the antibiotic-producing Actinobacteria. These bacteria produce several defensive chemicals with myriad uses, including one antibiotic that inhibits the growth of several bacterial strains, including other Actinobacteria. This antibiotic (known as nocamycin O) is a promising candidate for medicinal use due to its similarities to bacterial RNA polymerase inhibitors tirandamycin and streptolydigin, which inhibit several human pathogens. The determination of the structure of nocamycin O will be an ...
Docosanoic Acid Conjugation To Sirna Enables Functional And Safe Delivery To Skeletal And Cardiac Muscles, 2020 University of Massachusetts Medical School
Docosanoic Acid Conjugation To Sirna Enables Functional And Safe Delivery To Skeletal And Cardiac Muscles, Annabelle Biscans, Jillian Caiazzi, Nicholas Mchugh, Vignesh Hariharan, Manish Muhuri, Anastasia Khvorova
Open Access Publications by UMMS Authors
Oligonucleotide therapeutics hold promise for the treatment of muscle- and heart-related diseases. However, oligonucleotide delivery across the continuous endothelium of muscle tissue is challenging. Here, we demonstrate that docosanoic acid (DCA) conjugation of small interfering RNAs (siRNAs) enables efficient (~5% of injected dose), sustainable ( > 1 month), and non-toxic (no cytokine induction at 100 mg/kg) gene silencing in both skeletal and cardiac muscles after systemic injection. When designed to target myostatin (muscle growth regulation gene), siRNAs induced ~55% silencing in various muscle tissues and 80% silencing in heart, translating into a ~50% increase in muscle volume within 1 week. Our ...
Peptidylarginine Deiminase Inhibition Prevents Diabetes Development In Nod Mice, Fernanda M. C. Sodré, Samal Bissenova, Ylke Bruggeman, Ronak Tilvawala, Dana P. Cook, Claire Berthault, Santanu Mondal, Aïsha Callebaut, Sylvaine You, Raphael Scharfmann, Roberto Mallone, Paul R. Thompson, Chantal Mathieu, Mijke Buitinga, Lut Overbergh
Thompson Lab Publications
Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum ...
Coevolution, Dynamics And Allostery Conspire In Shaping Cooperative Binding And Signal Transmission Of The Sars-Cov-2 Spike Protein With Human Angiotensin-Converting Enzyme 2, Gennady M. Verkhivker
Mathematics, Physics, and Computer Science Faculty Articles and Research
Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of ...
Synthesis, In Vitro, And In Vivo Evaluation Of Novel N-Phenylindazolyl Diarylureas As Potential Anti-Cancer Agents., Lucas N Solano, Grady L Nelson, Conor T Ronayne, Shirisha Jonnalagadda, Sravan K Jonnalagadda, Kaija Kottke, Robert Chitren, Joseph L Johnson, Manoj K Pandey, Subash C. Jonnalagadda, Venkatram R Mereddy
Faculty Scholarship for the College of Science & Mathematics
Novel N-phenylindazole based diarylureas have been designed, synthesized and evaluated as potential anticancer agents. In vitro cell viability studies of these derivatives illustrate good potency with IC50 values in the range of 0.4–50 μM in several cancer cell lines including murine metastatic breast cancer 4T1, murine glioblastoma GL261, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal cancer cell line WiDr. The ester group in the lead compound 8i was modified to incorporate amino-amides to increase solubility and stability while retaining biological activity. Further in vitro studies reveal that lead candidates inhibit tube length ...