Design, Synthesis and Evaluation of AZA-peptide Epoxides as Inhibitors of Cysteine Proteases PDF Download
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Author: Iuliana L. Gheura
Publisher:
ISBN:
Category : Protease inhibitors
Languages : en
Pages : 338
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Book Description
Author: Iuliana L. Gheura
Publisher:
ISBN:
Category : Protease inhibitors
Languages : en
Pages : 338
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Book Description
Author: Amy J. Campbell
Publisher:
ISBN: 9781109870527
Category :
Languages : en
Pages : 162
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Book Description
This research involved the design, synthesis, and evaluation of irreversible cysteine protease inhibitors. Specifically, irreversible inhibitors of clan CA and clan CD cysteine proteases were studied. This research offers new and valuable insights into recently developed classes of inhibitors.
Author: Sylvia Shadinger Bridges
Publisher:
ISBN:
Category : Cysteine proteinases
Languages : en
Pages :
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Book Description
Proteases are enzymes that cleave protein amide bonds. Proteases are involved in a myriad of biological processes and are considered good targets for drug design. The proteases described herein are cysteine proteases, which utilize a cysteine residue thiol to attack the amide carbonyl, leading to amide bond cleavage. Irreversible inhibitors of cysteine proteases react with the active site cysteine, forming a covalent bond and rendering the enzyme inactive. The first project involved the design and synthesis of aza-peptide epoxide inhibitors for calpain, a clan CA, ubiquitous, calcium-activated human enzyme involved in neurodegeneration. These inhibitors proved to be poor inactivators of calpain, demonstrating that the aza-peptide epoxide is a warhead specific to clan CD cysteine proteases (caspases, gingipains). Subsequently, a known epoxide inhibitor of calpain was optimized to create a more potent inhibitor. Several of these inhibitors were more potent than the parent, and all were demonstrated to inhibit calpain in a breast cancer cell line which was treated with paclitaxel to spike calpain activity.
Author: Marion Gabriele Götz
Publisher:
ISBN:
Category : Biosynthesis
Languages : en
Pages :
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A second project focused on the epoxidation of the double bond of the vinyl sulfone moiety of the dipeptidyl vinyl sulfones. Instead of epoxidizing the double bond, we found that an isomerization had occurred. The newly formed compounds were determined to be allyl sulfones. We tested this new class of inhibitors with clan CA proteases and obtained inhibition rates of 560 M-1s-1 for Cbz-Leu-Phe-AS-Ph with calpain I. Two new classes of compounds for the clan CD protease S. mansoni legumain were designed, synthesized, and evaluated. Aza-peptidyl epoxides were found to be potent and selective inhibitors of S. mansoni legumain with IC50?s as low as 45 nM. Aza-peptide Michael acceptors were derived from the aza-peptide epoxide design and synthesized in an analogous fashion. The aza-peptide Michael acceptors inhibited S. mansoni legumain with even lower IC50?s, as low as 10 M. However, the aza-peptide Michael acceptors react with thioalkylating agents contained in the buffer, such as DTT. The rates of degradation were determined spectroscopically, and half-lives of 3 to 20 minutes were measured. This observation gave us insights into the enzymatic mechanism and allowed us to determine the point of attack for the legumain active site cysteine thiol.
Author: Asli Ovat
Publisher:
ISBN:
Category : Biosynthesis
Languages : en
Pages :
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Cysteine proteases are important drug targets due to their involvement in many biological processes such as protein turnover, digestion, blood coagulation, apoptosis, cell differentiation, cell signaling, and the immune response. In this thesis, we have reported the design, synthesis and evaluation of clan CA and clan CD cysteine protease inhibitors. Aza-peptidyl Michael acceptor and epoxide inhibitors for asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE) and the hard tick, Ixodes ricinus (IrAE) were designed and synthesized. SARs were similar, but with some notable exceptions. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1' position and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased inhibitory potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues in the P2 position. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors and, for some of these compounds, second order inhibition rate constants are the fastest yet discovered.
Author: Karen Amanda Ellis James
Publisher:
ISBN:
Category : Crysteine proteinase
Languages : en
Pages : 324
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Author: Anthony Kwabla Dotse
Publisher:
ISBN:
Category : Proteolytic enzymes
Languages : en
Pages : 396
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Author: Joel Anderson Krauser
Publisher:
ISBN:
Category : Protease inhibitors
Languages : en
Pages : 312
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Author: Stewart A. Thompson
Publisher:
ISBN:
Category :
Languages : en
Pages : 220
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Author: Leilani Milagros Lotti Diaz
Publisher:
ISBN:
Category : Multiple myeloma
Languages : en
Pages :
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Book Description
The proteasome is central to cellular protein regulation by degrading proteins conjugated to multiple units of the polypeptide ubiquitin. Due to their involvement in the regulation of apoptosis in cells and their abundance in multiple myeloma cells (MM), the proteasome has become a target for cancer treatment. Aza-peptide inhibitors are a new class of inhibitors designed to inhibit the proteasome and other proteases where a P1-amino acid and an electrophilic warhead comprise the potential therapeutic. Previous inhibitors of this type exhibited competitive inhibition of the 20S proteasome with Ki values in the micromolar range for in vitro studies and an IC50 value of 10–50 μM when screened against multiple myeloma and natural killer cell lines.49 In this thesis we present the synthesis and initial SAR studies of different sequences of proteasome-specific aza-peptide inhibitors with ketones and Michael acceptor warheads. We also present the tunability of these inhibitors by designing and synthesizing caspase-6 specific inhibitors. Our goals are to improve the potency and selectivity of aza-peptide inhibitors for optimal selectivity to their target enzymes.
