Design, Synthesis, and Evaluation of Irreversible Peptidyl Inhibitors for Clan CA and Clan CD Cysteine Proteases PDF Download
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Author: Marion Gabriele Götz
Publisher:
ISBN:
Category : Biosynthesis
Languages : en
Pages :
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Book Description
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: Marion Gabriele Götz
Publisher:
ISBN:
Category : Biosynthesis
Languages : en
Pages :
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Book Description
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: 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: 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: Asli Ovat
Publisher:
ISBN:
Category : Biosynthesis
Languages : en
Pages :
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Book Description
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:
Publisher:
ISBN:
Category : Dissertations, Academic
Languages : en
Pages : 924
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Author: American Chemical Society. Committee on Professional Training
Publisher:
ISBN:
Category : Biochemistry
Languages : en
Pages : 1932
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Faculties, publications and doctoral theses in departments or divisions of chemistry, chemical engineering, biochemistry and pharmaceutical and/or medicinal chemistry at universities in the United States and Canada.
Author: Iuliana L. Gheura
Publisher:
ISBN:
Category : Protease inhibitors
Languages : en
Pages : 338
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Author: Karen Amanda Ellis James
Publisher:
ISBN:
Category : Crysteine proteinase
Languages : en
Pages : 324
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Author: Stewart A. Thompson
Publisher:
ISBN:
Category :
Languages : en
Pages : 220
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Author: Joel Anderson Krauser
Publisher:
ISBN:
Category : Protease inhibitors
Languages : en
Pages : 312
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