Open Access. Powered by Scholars. Published by Universities.®

Medicinal-Pharmaceutical Chemistry Commons

Open Access. Powered by Scholars. Published by Universities.®

Chemicals and Drugs

Institution
Keyword
Publication Year
Publication
Publication Type
File Type

Articles 1 - 30 of 111

Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Mechanism For Apobec3g Catalytic Exclusion Of Rna And Non-Substrate Dna, William C. Solomon, Wazo Myint, Shurong Hou, Tapan Kanai, Rashmi Tripathi, Nese Kurt Yilmaz, Celia A. Schiffer, Hiroshi Matsuo Aug 2019

Mechanism For Apobec3g Catalytic Exclusion Of Rna And Non-Substrate Dna, William C. Solomon, Wazo Myint, Shurong Hou, Tapan Kanai, Rashmi Tripathi, Nese Kurt Yilmaz, Celia A. Schiffer, Hiroshi Matsuo

Schiffer Lab Publications

The potent antiretroviral protein APOBEC3G (A3G) specifically targets and deaminates deoxycytidine nucleotides, generating deoxyuridine, in single stranded DNA (ssDNA) intermediates produced during HIV replication. A non-catalytic domain in A3G binds strongly to RNA, an interaction crucial for recruitment of A3G to the virion; yet, A3G displays no deamination activity for cytidines in viral RNA. Here, we report NMR and molecular dynamics (MD) simulation analysis for interactions between A3Gctd and multiple substrate or non-substrate DNA and RNA, in combination with deamination assays. NMR ssDNA-binding experiments revealed that the interaction with residues in helix1 and loop1 (T201-L220) distinguishes the binding mode of ...


Molecular And Structural Mechanism Of Pan-Genotypic Hcv Ns3/4a Protease Inhibition By Glecaprevir, Jennifer Timm, Klajdi Kosovrasti, Mina Henes, Florian Leidner, Shurong Hou, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer Jul 2019

Molecular And Structural Mechanism Of Pan-Genotypic Hcv Ns3/4a Protease Inhibition By Glecaprevir, Jennifer Timm, Klajdi Kosovrasti, Mina Henes, Florian Leidner, Shurong Hou, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Hepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals (DAAs) had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes ...


Integration Of Random Forest Classifiers And Deep Convolutional Neural Networks For Classification And Biomolecular Modeling Of Cancer Driver Mutations, Steve Agajanian, Odeyemi Oluyemi, Gennady M. Verkhivker Jun 2019

Integration Of Random Forest Classifiers And Deep Convolutional Neural Networks For Classification And Biomolecular Modeling Of Cancer Driver Mutations, Steve Agajanian, Odeyemi Oluyemi, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Development of machine learning solutions for prediction of functional and clinical significance of cancer driver genes and mutations are paramount in modern biomedical research and have gained a significant momentum in a recent decade. In this work, we integrate different machine learning approaches, including tree based methods, random forest and gradient boosted tree (GBT) classifiers along with deep convolutional neural networks (CNN) for prediction of cancer driver mutations in the genomic datasets. The feasibility of CNN in using raw nucleotide sequences for classification of cancer driver mutations was initially explored by employing label encoding, one hot encoding, and embedding to ...


Determination Of Anxiolytic And Antidepressant Medicines In New York City Wastewater Samples, Jasmine J. Gayle May 2019

Determination Of Anxiolytic And Antidepressant Medicines In New York City Wastewater Samples, Jasmine J. Gayle

Student Theses

Wastewater-based epidemiology (WBE) provides information about a population’s exposure to certain chemical agents, such as drugs of abuse and medicines, by the analysis of human biomarkers, also known as excretion products, in wastewater samples. Although this is a growing field worldwide, mainly in Europe, Oceania, and Asia, limited data from the US are currently available. We developed and validated an analytical method to quantitatively and qualitatively determine the presence of commonly prescribed drugs to treat anxiety (alprazolam, buspirone, clonazepam, lorazepam, and propranolol) and depression (bupropion, citalopram, clomipramine, duloxetine, fluoxetine, imipramine, paroxetine, sertraline, and venlafaxine) in wastewater using liquid chromatography ...


Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed Mar 2019

Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed

Pharmacy Faculty Articles and Research

Ajwain (Trachyspermum ammi) belongs to the family Umbelliferae, is commonly used in traditional, and folk medicine due to its carminative, stimulant, antiseptic, diuretic, antihypertensive, and hepatoprotective activities. Non-specific lipid transfer proteins (nsLTPs) reported from various plants are known to be involved in transferring lipids between membranes and in plants defense response. Here, we describe the complete primary structure of a monomeric non-specific lipid transfer protein 1 (nsLTP1), with molecular weight of 9.66 kDa, from ajwain seeds. The nsLTP1 has been purified by combination of chromatographic techniques, and further characterized by mass spectrometry, and Edman degradation. The ajwain nsLTP1 is ...


Synthesis Of A Sulfur Variant For Treatment Of Trypanosomiasis, Carlos Vera-Esquivel Mar 2019

Synthesis Of A Sulfur Variant For Treatment Of Trypanosomiasis, Carlos Vera-Esquivel

Student Research and Creative Activity Fair

Previous work in our lab has found diphenyl ether benzylamines showed a successful response with a micromolar concentration of our lead compound to treat the deadly Trypanosamiosis rhodesience. Furthermore, mammalian cell lines saw promising resistance towards damages. The goal of this study was to synthesize a diphenyl thio benzylamine variant. This variant was more active toward T. b. rhodesience but showed more toxicity to both rat 10 (IC50 mM) and human cell lines (HFF, HC-04, U-2 OS, and HEK293). The selectivity index (ratio of toxicity to activity in the same concentration units (SI)) varied from 55 ...


Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Chromone/Aza-Chromone Fused Α-Aminophosphonates As Src Kinase Inhibitors, S. Bapat, N. Viswanadh, M. Mujahid, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, M. Karthikeyan, M. Muthukrishnan, Renu Vyas Feb 2019

Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Chromone/Aza-Chromone Fused Α-Aminophosphonates As Src Kinase Inhibitors, S. Bapat, N. Viswanadh, M. Mujahid, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, M. Karthikeyan, M. Muthukrishnan, Renu Vyas

Pharmacy Faculty Articles and Research

A series of novel chromone/aza-chromone fused α-aminophosphonate derivatives were synthesized in good yields using silica chloride as the catalyst. All the synthesized compounds were tested for their c-Src kinase inhibitory activity. Aza-chromone compound showed Src kinase inhibition with an IC50 value of 15.8 µM. The compounds were subjected to molecular docking and dynamics simulations to study the atomic level interactions with an unphosphorylated proto-oncogenic tyrosine protein kinase Src (PDB code 1Y57) as well as phosphorylated tyrosine protein kinase Src (PDB code 2H8H). Docking and molecular dynamic results revealed phosphorylated Src tyrosine kinase protein better results than unphosphorylated tyrosine ...


Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson Dec 2018

Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson

University of Massachusetts Medical School Publications

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAD4 in TLR-7-dependent lupus autoimmunity were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, immune ...


Functional Features Defining The Efficacy Of Cholesterol-Conjugated, Self-Deliverable, Chemically Modified Sirnas, Taisia Shmushkovich, Kathryn R. Monopoli, Diana Homsy, Dmitriy Leyfer, Monica Betancur-Boissel, Anastasia Khvorova, Alexey D. Wolfson Nov 2018

Functional Features Defining The Efficacy Of Cholesterol-Conjugated, Self-Deliverable, Chemically Modified Sirnas, Taisia Shmushkovich, Kathryn R. Monopoli, Diana Homsy, Dmitriy Leyfer, Monica Betancur-Boissel, Anastasia Khvorova, Alexey D. Wolfson

Open Access Articles

Progress in oligonucleotide chemistry has produced a shift in the nature of siRNA used, from formulated, minimally modified siRNAs, to unformulated, heavily modified siRNA conjugates. The introduction of extensive chemical modifications is essential for conjugate-mediated delivery. Modifications have a significant impact on siRNA efficacy through interference with recognition and processing by RNAi enzymatic machinery, severely restricting the sequence space available for siRNA design. Many algorithms available publicly can successfully predict the activity of non-modified siRNAs, but the efficiency of the algorithms for designing heavily modified siRNAs has never been systematically evaluated experimentally. Here we screened 356 cholesterol-conjugated siRNAs with extensive ...


Drug Resistance Mutation L76v Alters Nonpolar Interactions At The Flap-Core Interface Of Hiv-1 Protease, Andres Wong-Sam, Yuan-Fang Wang, Ying Zhang, Arun K. Ghosh, Robert W. Harrison, Irene T. Weber Sep 2018

Drug Resistance Mutation L76v Alters Nonpolar Interactions At The Flap-Core Interface Of Hiv-1 Protease, Andres Wong-Sam, Yuan-Fang Wang, Ying Zhang, Arun K. Ghosh, Robert W. Harrison, Irene T. Weber

RNA Therapeutics Institute Publications

Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best K i value of 1.9 nM for PRL76V, whereas the other three inhibitors had K i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with ...


Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington Sep 2018

Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington

University of Massachusetts Medical School Publications

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone ...


Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din Aug 2018

Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes ...


Citrullination Inactivates Nicotinamide-N-Methyltransferase, Venkatesh V. Nemmara, Ronak Tilvawala, Ari J. Salinger, Lacey Miller, Son Hong Nguyen, Eranthie Weerapana, Paul R. Thompson Jul 2018

Citrullination Inactivates Nicotinamide-N-Methyltransferase, Venkatesh V. Nemmara, Ronak Tilvawala, Ari J. Salinger, Lacey Miller, Son Hong Nguyen, Eranthie Weerapana, Paul R. Thompson

Thompson Lab Publications

Nicotinamide-N-methyl transferase (NNMT) catalyzes the irreversible methylation of nicotinamide (NAM) to form N-methyl nicotinamide (MeNAM) using SAM as a methyl donor. NNMT is implicated in several chronic disease conditions, including cancers, kidney disease, cardiovascular disease, and Parkinson's disease. Although phosphorylation of NNMT in gastric tumors is reported, the functional effects of this post-translational modification has not been investigated. We previously reported that citrullination of NNMT by Protein Arginine Deiminases (PADs) abolished its methyltransferase activity. Herein, we investigate the mechanism of inactivation. Using tandem MS, we identified three sites of citrullination in NNMT. With this information in hand, we used ...


Photochemical Investigation Of High-Valent Metal-Oxo Intermediates Containing Corrole And Light-Harvesting Porphyrin Ligands, Jonathan Malone Jul 2018

Photochemical Investigation Of High-Valent Metal-Oxo Intermediates Containing Corrole And Light-Harvesting Porphyrin Ligands, Jonathan Malone

Masters Theses & Specialist Projects

In enzymatic and synthetic catalytic oxidations, high-valent iron-oxo intermediates play a vital role as the active oxidant. In this regard, many synthetic metal catalysts are designed as biomimetic models to resemble the active site of Cytochrome P450 enzymes (P450) which are the predominant oxidation catalysts in nature. Vitamin B12 cofactors, with a corrole-like structure corrin, are also utilized in some of the more difficult reactions in nature such as rearrangement and reductase reactions.

In this work, application of the promising photochemical method to corrolecontaining ligands systems showed much success in the generation of manganese(V)-oxo corrole intermediates using two ...


Microgel Core/Shell Architectures As Targeted Agents For Fibrinolysis, Purva Kodlekere, L. Andrew Lyon Jun 2018

Microgel Core/Shell Architectures As Targeted Agents For Fibrinolysis, Purva Kodlekere, L. Andrew Lyon

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

We demonstrate the utility of microgel core/shell structures conjugated to fibrin-specific peptides as fibrinolytic agents. Poly(N-isopropylmethacrylamide) (pNIPMAm) based microgels conjugated to the peptide GPRPFPAC (GPRP) were observed to bring about fibrin clot erosion, merely through exploitation of the dynamic nature of the clots. These results suggest the potential utility of peptide–microgel hybrids in clot disruption and clotting modulation.


Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer Jun 2018

Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer

Schiffer Lab Publications

C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin-remodeling enzymes to gene promoters. The NAD(H)-linked oligomerization of human CtBP is coupled to its co-transcriptional activity, which is implicated in cancer progression. However, the biologically relevant level of CtBP assembly has not been firmly established; nor has the stereochemical arrangement of the subunits above that of a dimer. Here, multi-angle light scattering (MALS) data established the NAD(+)- and NADH-dependent assembly of CtBP1 and CtBP2 into tetramers. An examination of subunit interactions within CtBP1 ...


Preparation Of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles For Pharmaceutical Applications, Kate E. Frischkorn Jun 2018

Preparation Of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles For Pharmaceutical Applications, Kate E. Frischkorn

Master's Theses and Project Reports

Recent pharmaceutical developments have investigated using supramolecular nanoparticles in order to increase the bioavailability and solubility of drugs delivered in various methods. Modification of the carbohydrate cyclodextrin increases the ability to encapsulate hydrophobic pharmaceutical molecules by forming a carrier with a hydrophobic core and hydrophilic exterior. Guest molecules are commonly added to these inclusion complexes in order to add stability and further increase targeting abilities of the carriers. One such guest molecule is adamantine combined with a poly(ethylene glycol) chain. Vesicles are formed by hydrating a thin film of amphiphilic cyclodextrin and guest molecules in buffer solution that mimics ...


Dissecting Structure-Encoded Determinants Of Allosteric Cross-Talk Between Post-Translational Modification Sites In The Hsp90 Chaperones, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker May 2018

Dissecting Structure-Encoded Determinants Of Allosteric Cross-Talk Between Post-Translational Modification Sites In The Hsp90 Chaperones, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs ...


Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson Apr 2018

Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson

Thompson Lab Publications

Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and breast cancer. Therefore, the development of PAD-inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD-inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-Amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis-isomer of 1 is 10-fold more potent than its trans-isomer, whereas the trans-isomer of ...


Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow Apr 2018

Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow

Open Access Articles

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of ...


Organocatalyzed Synthesis Of Epoxides From Chalcones Utilizing Amino Acids, Sabrina N. Kegeler Apr 2018

Organocatalyzed Synthesis Of Epoxides From Chalcones Utilizing Amino Acids, Sabrina N. Kegeler

Master's Theses

The epoxide functional group is important throughout the chemical and pharmaceutical industries, as well as in nature. In the chemical industry, epoxides are present in resins and fragrances. In the pharmaceutical industry, epoxide-containing compounds are used as intermediates in the manufacturing of drugs. In nature, many natural products contain epoxide groups and are used for medicinal purposes, and for models to create synthetic molecules.

One approach to epoxide synthesis involves the use of an alkene precursor, a base, and an oxidizing agent. This is where my investigations began. The first step was to optimize the epoxidation reaction, examining substrate scope ...


The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson Mar 2018

The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson

Thompson Lab Publications

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and "clickable" probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced ...


Comparison Of Partially And Fully Chemically-Modified Sirna In Conjugate-Mediated Delivery In Vivo, Matthew R. Hassler, Anton A. Turanov, Julia F. Alterman, Reka A. Haraszti, Andrew H. Coles, Maire F. Osborn, Dimas Echeverria, Mehran Nikan, William E. Salomon, Loic Roux, Bruno M. D. C. Godinho, Sarah M. Davis, David V. Morrissey, Phillip D. Zamore, S. Ananth Karumanchi, Melissa J. Moore, Neil Aronin, Anastasia Khvorova Feb 2018

Comparison Of Partially And Fully Chemically-Modified Sirna In Conjugate-Mediated Delivery In Vivo, Matthew R. Hassler, Anton A. Turanov, Julia F. Alterman, Reka A. Haraszti, Andrew H. Coles, Maire F. Osborn, Dimas Echeverria, Mehran Nikan, William E. Salomon, Loic Roux, Bruno M. D. C. Godinho, Sarah M. Davis, David V. Morrissey, Phillip D. Zamore, S. Ananth Karumanchi, Melissa J. Moore, Neil Aronin, Anastasia Khvorova

Open Access Articles

Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various ...


The Forensic Characterization Of Bacterial And Fungal Organisms In Traditional Chinese Medicine, Julia Grzymkowski, Christopher J. Ehrhardt, Justin L. Poklis, Michelle R. Peace Jan 2018

The Forensic Characterization Of Bacterial And Fungal Organisms In Traditional Chinese Medicine, Julia Grzymkowski, Christopher J. Ehrhardt, Justin L. Poklis, Michelle R. Peace

Undergraduate Research Posters

There has been an increase in use of Traditional Chinese Medicine (TCM) in the United States because they are less expensive and believed to be more effective with less adverse effects in comparison to traditional pharmaceutics. Therefore, sales have increased in the US, despite articles and case studies demonstrating the dangers, such as injury and death, related to TCM, stemming from improper labelling, toxic contaminants, and, in some cases, the presence of pathogenic bacteria. The aim of this study was to perform a survival experiment to demonstrate the importance of proper herbal brewing technique and to conduct a molecular and ...


Ensemble-Based Modeling And Rigidity Decomposition Of Allosteric Interaction Networks And Communication Pathways In Cyclin-Dependent Kinases: Differentiating Kinase Clients Of The Hsp90-Cdc37 Chaperone, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker Nov 2017

Ensemble-Based Modeling And Rigidity Decomposition Of Allosteric Interaction Networks And Communication Pathways In Cyclin-Dependent Kinases: Differentiating Kinase Clients Of The Hsp90-Cdc37 Chaperone, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK ...


Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury Jul 2017

Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions ofmenthol. There has been new evidence demonstrating thatmenthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at ...


Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer Jul 2017

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer Jun 2017

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky Jun 2017

Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Thompson Lab Publications

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a ...


Detection Of Cathinone And Mephedrone In Plasma By Lc-Ms/Ms Using Standard Addition Quantification Technique, Theron W. Ng-A-Qui May 2017

Detection Of Cathinone And Mephedrone In Plasma By Lc-Ms/Ms Using Standard Addition Quantification Technique, Theron W. Ng-A-Qui

Student Theses

Designer drugs are structural analogs of Drug Enforcement Agency (DEA) Schedule I and II substances. They are synthesized to mimic the effects of illegal drugs of abuse and to bypass the provisions of drug regulations. Despite the increased availability of designer drugs, few studies have focused on specific analytical extraction techniques for their detection and quantification in biological samples. Solid phase extraction (SPE) is the most commonly used technique for sample preparation. The purpose of this study is to evaluate the extraction efficiency of the various SPE columns with different sorbent materials for two designer drugs, cathinone and mephedrone in ...