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Peptide Drug Discovery: Innovative Technologies And Transformational Medicines, David J. Diller, Mark Jarosinski, Tomi K. Sawyer, Joseph Audie 2016 Sacred Heart University

Peptide Drug Discovery: Innovative Technologies And Transformational Medicines, David J. Diller, Mark Jarosinski, Tomi K. Sawyer, Joseph Audie

Joseph Audie

Interest in peptide drug discovery is surging. In the past several years,numerous pharmaceutical and biotech companies have committed considerable resources to peptide-based drug discovery. In part,this is being fueled by an increasing recognition that peptide drugs combine many of the virtues of small molecules and proteins, while minimizing several of their drawbacks, and that peptides can potentially expand the druggable space to include intracellular, extracellular and membrane associated protein–protein interactions. Moreover, powerful new in vitro and in silico technologies and breakthroughs in our understanding of natural peptides have emerged that provide peptide chemists with the toolsand insights ...


Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. McKeon, Alan Egan, Jay Chandanshive, Helena McMahon, Darren M. Griffith 2016 Royal College of Surgeons in Ireland

Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith

Pharmaceutical and Medicinal Chemistry Articles

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.


Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver 2016 DePaul University

Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver

DePaul Discoveries

Caspase-1 is an enzyme that is overactive in autoimmune and autoinflammatory diseases cleaving pro-interleukin-1β to the cytokine interleukin-1β (IL-1β), which leads to inflammatory symptoms. The inhibition of caspase-1 will cause a decrease in the concentration of interleukin-1β (IL-1β), resulting in the reduction of inflammatory symptoms. Recent research has revealed that the appending of a nitric oxide (NO) or nitroxyl (HNO) donating group to non-steroidal anti-inflammatory drugs (NSAIDs) reduced, or avoided, the side effects caused by currently available treatments. A small molecule based on a known caspase-1 inhibitor with a nitrosocysteine appended on was synthesized to look at the effect of ...


Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian 2016 University of Massachusetts Medical School

Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian

UMass Center for Clinical and Translational Science Research Retreat

Soil-transmitted helminths (STHs), most notably, hookworms, whipworms, and Ascaris, are nematodes that infect more than 1.5 billion of the poorest people and are amongst the leading causes of morbidity worldwide. Only two classes of de-worming drugs (anthelmintics) are available for treatment, and only one is commonly used in mass drug administrations. New anthelmintics are urgently needed to overcome emerging resistance and to produce higher cure rates. Crystal (Cry) proteins, in particular Cry5B, made by Bacillus thuringiensis (Bt) are promising new candidates. Cry5B has excellent anthelmintic properties against many free-living and parasitic nematodes, including in vivo efficacy against multiple STH ...


Structural Activity Relationship Study On Dual Plk1 /Brd4 Inhibitor, Bi- 2536, Hailemichael Yosief, Shuai Liu, Dennis L. Buckley, Justin M. Roberts, Alex M. Muthengi, Francesca M. Corsini, James E. Bradner, Wei Zhang 2016 University of Massachusetts Boston

Structural Activity Relationship Study On Dual Plk1 /Brd4 Inhibitor, Bi- 2536, Hailemichael Yosief, Shuai Liu, Dennis L. Buckley, Justin M. Roberts, Alex M. Muthengi, Francesca M. Corsini, James E. Bradner, Wei Zhang

UMass Center for Clinical and Translational Science Research Retreat

Polo-like kinase 1 (PLK1) and BRD4 are two different therapeutic targets in cancer drug discovery. Recently it has been reported that PLK1 inhibitor, BI-2536, is also a potent inhibitor of BRD4. The simultaneous inhibition of PLK1 and BRD4 by a single drug molecule is interesting because this could lead to the development of effective therapeutic strategy for different types of disease conditions in which PLK1 and BRD4 are implicated. Structural activity relationship studies has been carried out on BI-2536 to generate analogs with enhanced dual inhibitory activity against BRD4 and PLK1 as well as to render the molecule selective to ...


Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török 2016 University of Massachusetts Boston

Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török

UMass Center for Clinical and Translational Science Research Retreat

Diaryl hydrazones, possessing similar structure to the popular red wine antioxidant resveratrol, have been previously identified as multitarget compounds interfering with several processes associated with the pathogenesis of Alzheimer’s disease (AD). These compounds exhibited particularly strong inhibition of the amyloid beta (A) peptide self-assembly, including blocking the formation of fibrils and oligomers, species that are widely accepted to be neurotoxic. The molecules were also powerful free radical scavengers and thus have a potential to defend against oxidative stress.

In order to learn more about the mode of action of the compounds, theoretical and experimental studies have been carried out ...


Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff 2016 University of Massachusettts Medical School

Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-Thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff

UMass Center for Clinical and Translational Science Research Retreat

There is an urgent need for new therapies for parasitic helminthic diseases affecting 1.5-2 billion people worldwide due to the threat of wide-spread resistance development to existing treatments and due to problems of incomplete efficacies.

Terpenes are plant secondary metabolites and major essential oil constituents. Historically, the terpene thymol was successfully used to cure hookworm infections in the 1900’s. Although effective, large doses were needed and thymol treatment had significant side effects. Because free terpenes are absorbed in the stomach, less than 10% of oral terpenes entered the site where the parasites live. To overcome these problems we ...


Synthesis Of A Novel Cox-2 Inhibitor Analog For Pet Scan Imaging, Rebecca Neighbor 2016 University of Tennessee, Knoxville

Synthesis Of A Novel Cox-2 Inhibitor Analog For Pet Scan Imaging, Rebecca Neighbor

University of Tennessee Honors Thesis Projects

No abstract provided.


Staphylococcal Nuclease And Ubiquitin Local Folding Energies And Rates Using Peps-Hdx-Esi-Ms, Julie Rhee 2016 University of Arkansas, Fayetteville

Staphylococcal Nuclease And Ubiquitin Local Folding Energies And Rates Using Peps-Hdx-Esi-Ms, Julie Rhee

Chemistry & Biochemistry Undergraduate Honors Theses

In this study, Protein Equilibrium Population Snapshot Hydrogen-Deuterium Exchange Electrospray Ionization Mass Spectrometry (PEPS-HDX-ESI-MS) was applied to study the local regions of model proteins, staphylococcal nuclease and ubiquitin. The hydrogen deuterium exchange (HDX) has become a key technique for studying the structural and dynamic aspects of proteins in solution. This technique creates a rapid exchange between all of the exchangeable hydrogen ions with deuterium when the protein is exposed to a solvent. The PEPS method is an equilibrium-based method used to determine the populations of the closed native and open denatured states of a protein. By combining the applications of ...


Catalytic Transfer Hydrogenation Of Nitroalkenes To Primary Amines, Brendan Phillips 2016 Ursinus College

Catalytic Transfer Hydrogenation Of Nitroalkenes To Primary Amines, Brendan Phillips

Chemistry Honors Papers

This work describes synthetic methodology development in organic chemistry. The goal of this work is to demonstrate new ways of making biologically-relevant molecules that are in line with the principles of green chemistry (chemical practices which seek to be, regarding human and environmental health, benign by design). To this end, a new method has been developed toward the introduction of primary amine functionalities into organic molecules from readily-available aldehydes, via reduction of nitroalkene intermediates. Traditional methods of reducing nitroalkenes to primary amines require harsh conditions, often produce stoichiometric amounts of metal salt waste, and present significant safety challenges to the ...


Comparison Of Conventional And Microwave-Assisted Synthesis Of Chemokine Receptor Type 4 (Cxcr4) Antagonists, Saniya Virani, Damilola Gbadebo, Theresa D. Gaines, Francisco Javier Garcia 2016 Georgia State University

Comparison Of Conventional And Microwave-Assisted Synthesis Of Chemokine Receptor Type 4 (Cxcr4) Antagonists, Saniya Virani, Damilola Gbadebo, Theresa D. Gaines, Francisco Javier Garcia

Georgia State Undergraduate Research Conference

No abstract provided.


Analysis Of New Hiv-1 Inhibitors As Potential Antiviral Agents For Hiv-2, Rowan Brothers 2016 Georgia State University

Analysis Of New Hiv-1 Inhibitors As Potential Antiviral Agents For Hiv-2, Rowan Brothers

Georgia State Undergraduate Research Conference

No abstract provided.


Binding Of Oxaliplatin And Its Analogs With Dna Nucleotides At Variable Ph And Concentration Levels, Rippa Sehgal 2016 Western Kentucky University

Binding Of Oxaliplatin And Its Analogs With Dna Nucleotides At Variable Ph And Concentration Levels, Rippa Sehgal

Masters Theses & Specialist Projects

Oxaliplatin is one of the three FDA-approved platinum anticancer drugs and considered a third generation drug, discovered after the first generation drug cisplatin and second generation drug carboplatin. It is known to react with proteins and DNA nucleotides in the body. Reaction with DNA occurs primarily at guanosine residues and secondarily at adenine residues for oxaliplatin and other platinum drugs. We have previously studied oxaliplatin and an analog with additional steric hindrance in the amine ligand and found that the analog had different reactivity with methionine. Now, we have prepared oxaliplatin and its three analogs Pt(Me2dach)(ox), Pt(en ...


A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin 2016 University of Dayton

A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin

Albert Fratini

The title compound, sodium bis­(6-carb­oxy-1-hy­droxy-3-oxo-1,3-dihydro-2,1-benzoxaborol-1-yl)oxidanium, Na+·C16H15B2O13-, was prepared in two steps from 2-bromo-p-xylene. Its crystal structure was determined at 140 K and has triclinic (P) symmetry. The compound presents a unique structural motif, including two units of the cyclic anhydride of boronoterephthalic acid, joined by a protonated, and thereby trivalent, oxonium center. Association in the crystal is realized by complementary hydrogen bonding of the carboxyl groups, as well as by coordination of the sodium cations to the oxygen centers on the five-membered rings.


Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson 2016 The Scripps Research Institute

Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson

Thompson Lab Publications

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states.


“Zipped Synthesis” By Cross-Metathesis Provides A Cystathionine Β‑Synthase Inhibitor That Attenuates Cellular H2S Levels And Reduces Neuronal Infarction In A Rat Ischemic Stroke Model, Christopher D. McCune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.-H. Wong, David B. Berkowitz 2016 University of Nebraska-Lincoln

“Zipped Synthesis” By Cross-Metathesis Provides A Cystathionine Β‑Synthase Inhibitor That Attenuates Cellular H2S Levels And Reduces Neuronal Infarction In A Rat Ischemic Stroke Model, Christopher D. Mccune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.-H. Wong, David B. Berkowitz

David Berkowitz Publications

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics ...


The Design And Synthesis Of Ghrelin Analogues As Non‐Invasive Ghs‐R1a Imaging Probes, Carlie L. Charlton 2016 The University of Western Ontario

The Design And Synthesis Of Ghrelin Analogues As Non‐Invasive Ghs‐R1a Imaging Probes, Carlie L. Charlton

Electronic Thesis and Dissertation Repository

The field of molecular imaging is constantly growing and evolving in order to provide the best possible healthcare for patients in various stages of disease and therapy. Molecular imaging aims to locate specific markers of disease by selectively targeting the markers of interest with high selectivity and visualizing the accumulation using external detection. The growth hormone secretagogue receptor-1a (GHS-R1a) has been shown to be involved in various important biological functions such as energy homeostasis and cardiac contractility. GHS-R1a has shown involvement in proliferation, migration and cell invasion of specific cancer subtypes. Therefore, targeting GHS-R1a is an important marker of different ...


Synthesis Of Novel Aporphine-Inspired Neuroreceptor Ligands, Nirav R. Kapadia 2016 Graduate Center, City University of New York

Synthesis Of Novel Aporphine-Inspired Neuroreceptor Ligands, Nirav R. Kapadia

All Graduate Works by Year: Dissertations, Theses, and Capstone Projects

Aporphines are a group of tetracyclic alkaloids that belong to the ubiquitous tetrahydroisoquinoline family. The aporphine template is known to be associated with a range of biological activities. Aporphines have been explored as antioxidants, anti-tuberculosis, antimicrobial and anticancer agents. Within the Central Nervous Systems (CNS), aporphine alkaloids are known to possess high affinity for several clinically valuable targets including dopamine receptors (predominantly D1 and D2), serotonin receptors (5-HT1A and 5-HT7) and α adrenergic receptors. Aporphines are also inhibitors of the acetylcholinesterase enzyme – a clinical target for the treatment of Alzheimer’s disease. Considering the diverse profile ...


The Ssdna Mutator Apobec3a Is Regulated By Cooperative Dimerization, Markus-Frederik Bohn, Shivender Shandilya, Tania Silvas, Ellen Nalivaika, Takahide Kouno, Brian Kelch, Sean Ryder, Nese Yilmaz, Mohan Somasundaran, Celia Schiffer 2016 University of Massachusetts Medical School

The Ssdna Mutator Apobec3a Is Regulated By Cooperative Dimerization, Markus-Frederik Bohn, Shivender Shandilya, Tania Silvas, Ellen Nalivaika, Takahide Kouno, Brian Kelch, Sean Ryder, Nese Yilmaz, Mohan Somasundaran, Celia Schiffer

Celia A. Schiffer

Deaminase activity mediated by the human APOBEC3 family of proteins contributes to genomic instability and cancer. APOBEC3A is by far the most active in this family and can cause rapid cell death when overexpressed, but in general how the activity of APOBEC3s is regulated on a molecular level is unclear. In this study, the biochemical and structural basis of APOBEC3A substrate binding and specificity is elucidated. We find that specific binding of single-stranded DNA is regulated by the cooperative dimerization of APOBEC3A. The crystal structure elucidates this homodimer as a symmetric domain swap of the N-terminal residues. This dimer interface ...


Structure Of The Vif-Binding Domain Of The Antiviral Enzyme Apobec3g, Takahide Kouno, Elizabeth Luengas, Megumi Shigematsu, Shivender Shandilya, JingYing Zhang, Luan Chen, Mayuko Hara, Celia Schiffer, Reuben Harris, Hiroshi Matsuo 2016 University of Massachusetts Medical School

Structure Of The Vif-Binding Domain Of The Antiviral Enzyme Apobec3g, Takahide Kouno, Elizabeth Luengas, Megumi Shigematsu, Shivender Shandilya, Jingying Zhang, Luan Chen, Mayuko Hara, Celia Schiffer, Reuben Harris, Hiroshi Matsuo

Celia A. Schiffer

The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation. Although the structure of the A3G catalytic domain is known, the structure of the N-terminal Vif-binding domain has proven more elusive. Here, we used evolution- and structure-guided mutagenesis to solubilize the Vif-binding domain of A3G, thus permitting structural determination by NMR spectroscopy. A smaller zinc-coordinating pocket and altered helical packing distinguish the structure from previous catalytic-domain structures and help to explain the reported inactivity of this domain. This soluble A3G N-terminal domain is bound by ...


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