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Title
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Design, synthesis and characterization of α-amino diaryl phosphonates as serine protease inhibitors with applications in antimicrobial drug discovery
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Author
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Abstract
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| The serine protease family is the most widely studied group of proteins in biology. These enzymes are of special interest due to their notoriously diverse and well-characterized role in physiological and pathological processes. Under normal circumstances, complex and accurate systems regulate the proteolytic activity of serine proteases. Dysregulation of their function results in pathological disorders. Diaryl esters of a-amino phosphonates are a group of irreversible inhibitors of serine proteases. Their potent inhibition of serine proteases added to their absolute lack of activity against cysteine or threonine proteases confer them advantage over alternative serine protease inhibitors lacking this selectivity such as chloromethyl ketones, ketoesters or ketoamides. These attributes open for them a broad range of applications in the Medicinal Chemistry field, from the design of small molecules for target inhibition, to the synthesis of chemical tools such as ABPs. The focus of this PhD research lies on these two options. Design, synthesis and characterization of small inhibitors was undertaken for the antimicrobial drug discovery field. Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress-response and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition and a chemical exploration around the hit compounds was conducted. Altogether 14 new potent inhibitors of E. coli ClpP were identified. Compounds 4.85 and 4.92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile. Utilization of a-amino diaryl phosphonates as chemical tools for the target identification was the second goal of this PhD research, focusing on the design and synthesis of activity-based probes for serine proteases involved in the patho-physiological mechanism of visceral hypersensitivity. Establishment of an efficient synthetic route with the potential of combining a variety of reporter tags in a last step was achieved. A small library of 12 ABPs with an acceptable inhibitory activity for different subclasses of serine proteases was synthesized. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences, Department of Pharmaceutical Sciences
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2019
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Volume/pages
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335 p.
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Note
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Augustyns, Koen [Supervisor]
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De Winter, Hans [Supervisor]
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Full text (publisher's version - intranet only)
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