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You searched for subject:(WaterLOGSY). Showing records 1 – 2 of 2 total matches.

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Dalhousie University

1. Martinez-Farina, Camilo. Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins.

Degree: MS, Department of Chemistry, 2015, Dalhousie University

Nature produces many clinically used medicines in the form of natural products. These compounds can be isolated from a variety of sources, but bacteria have been shown to be the most prolific source. The strain Streptomyces has been thoroughly investigated for such natural products, with Streptomyces venezuelae ISP5230 showing the ability to produce the clinically used antibiotic chloramphenicol, as well as the jadomycins, a family of secondary metabolites. These secondary metabolites are produced through a biosynthetic pathway where the incorporation of the amino acid into the jadomycin structure is likely non-enzymatic. This allows for jadomycins to be readily derivatized, where upwards of twenty-five derivatives have been previously isolated. This work presents the amplification of the jadomycin library through the production of novel jadomycins, as well as their further diversification through the use of synthetic derivatization. The study of jadomycins is not only important chemically, but also biologically because they have been shown to possess anti-cancerous properties. For this reason, the two synthetic derivatives were assessed for biological activities and their results are discussed herein. Investigations were also carried out to develop a method to assess biological activity by nuclear magnetic resonance, and are presented. Finally, investigations into the jadomycin purification methodology were carried out using JadX, a potential regulatory protein in the jadomycin biosynthesis, and are discussed. Advisors/Committee Members: n/a (external-examiner), Dr. Mark Stradiotto (graduate-coordinator), Dr. T. Bruce Grindley (thesis-reader), Dr. Frances L. Cozens (thesis-reader), Dr. David L. Jakeman (thesis-supervisor), Not Applicable (ethics-approval), Yes (manuscripts), Yes (copyright-release).

Subjects/Keywords: Natural Products; Jadomycin; Precursor-Directed Biosynthesis; WaterLOGSY

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Martinez-Farina, C. (2015). Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins. (Masters Thesis). Dalhousie University. Retrieved from http://hdl.handle.net/10222/56323

Chicago Manual of Style (16th Edition):

Martinez-Farina, Camilo. “Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins.” 2015. Masters Thesis, Dalhousie University. Accessed May 29, 2020. http://hdl.handle.net/10222/56323.

MLA Handbook (7th Edition):

Martinez-Farina, Camilo. “Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins.” 2015. Web. 29 May 2020.

Vancouver:

Martinez-Farina C. Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins. [Internet] [Masters thesis]. Dalhousie University; 2015. [cited 2020 May 29]. Available from: http://hdl.handle.net/10222/56323.

Council of Science Editors:

Martinez-Farina C. Investigations into the Biosynthesis, Derivatization, and Purification of Jadomycins. [Masters Thesis]. Dalhousie University; 2015. Available from: http://hdl.handle.net/10222/56323


University of Illinois – Chicago

2. Lei, Hao. Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease.

Degree: 2016, University of Illinois – Chicago

The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study, we adopted a fragment-based hit discovery approach, using three screening methods − saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, KD) of these compounds varied between 234 and 301 μM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3,000 computationally pre-selected fragments. Fifteen final fragment hits were confirmed to exhibit binding affinities varying from 14 μM to 900 μM, which were categorized into five different basic scaffolds. All fifteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme. Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) is known to be essential for viral replication, making it an attractive target in antiviral drug discovery. In our study, we explored and optimized the MERS-PLpro crystallization condition. Two structures were solved with resolutions at 2.59 Å and 1.79 Å, respectively. The overall structure of MERS-PLpro resembles that of SARS-PLpro. The MERS-PLpro blocking loop 2 (BL2) structure differs significantly from that of SARS-PLpro, where it plays a crucial role in inhibitor binding. Four SARS-PLpro lead inhibitors with IC50 values ranging from 0.2 to 2.0 µM were tested against MERS-PLpro, none of which were effective against MERS-PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-PLpro were replaced by T274 and A275 in MERS-PLpro, eliminating critical binding interactions for similar types of inhibitors. High-throughput screening (HTS) of 25,000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. This newly identified compound acts as a competitive inhibitor with an IC50 of 6 µM against MERS-PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-PLpro with an IC50 of 11 µM. Docking studies were performed to predict the possible interactions between inhibitor and both SARS and MERS-PLpro. These results demonstrate that inhibitor recognition specificity of MERS-PLpro differs from that of SARS-PLpro. In addition, mutagenesis studies… Advisors/Committee Members: Johnson, Michael E. (advisor), Moore, Terry W. (committee member), Burdette, Joanna E. (committee member), Caffrey, Michael S. (committee member), Murphy, Brian T. (committee member).

Subjects/Keywords: PurE; Purine biosynthesis; Bacillus anthracis; STD-NMR; WaterLOGSY NMR; SPR; Fragment-based drug design; Coronavirus; MERS; Papain-like protease; Crystallography; High throughput screening; Enzyme inhibitor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lei, H. (2016). Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/20892

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Lei, Hao. “Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease.” 2016. Thesis, University of Illinois – Chicago. Accessed May 29, 2020. http://hdl.handle.net/10027/20892.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Lei, Hao. “Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease.” 2016. Web. 29 May 2020.

Vancouver:

Lei H. Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease. [Internet] [Thesis]. University of Illinois – Chicago; 2016. [cited 2020 May 29]. Available from: http://hdl.handle.net/10027/20892.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lei H. Inhibitor Development for Bacterial N5-CAIR Mutase and MERS Coronavirus Papain-like Protease. [Thesis]. University of Illinois – Chicago; 2016. Available from: http://hdl.handle.net/10027/20892

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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