Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/126464
Type: Thesis
Title: Inhibition of serine and cysteine proteases by peptidomimetic inhibitors
Author: Schumann, Nicholas
Issue Date: 2017
School/Discipline: School of Physical Sciences
Abstract: Proteases are responsible for the hydrolysis of proteins and peptides and have been implicated in the development of various diseases. Herein describes the design and synthesis of reversible peptidomimetic inhibitors of serine and cysteine protease for the control of protease activity. Proteases recognise substrates’ secondary peptide structure which conforms to a saw-tooth arrangement of amino acids, known as an extended β-strand geometry. This property has led to the development of potent inhibitors which mimic this conformation. Chapter two discusses defining β-strand geometry in inhibitors, while maintaining key substituents necessary for recognition by protease hosts, by the replacement of N-terminal residues with heterocyclic constraints. The inclusion of a heterocycle both enforces backbone β-strand conformation while increasing inhibitor bioavailability and metabolic stability. A series of peptidomimetic inhibitors containing heterocycles, including pyrrole, furan, thiophene and pyridine were synthesised, and the associated inhibitory activities against a model serine protease, α-Chymotrypsin, determined in proteolytic assays. Of the series of heterocycles, pyrrole was determined to be the optimum heterocycle for inclusion in inhibitors of this class. Extension of this concept of constraint was investigated in the approach towards heterocycle-containing macrocycles constructed by ring-closing metathesis for the inhibition of cysteine Cathepsin proteases, where the introduction of a macrocyclic tether couples with the heterocyclic constraint to define the desired backbone β-strand geometry. Pyrrole-containing macrocycle 2.47 was constructed by ring-closing metathesis, but was found to be unstable to hydrogenation conditions. A similar pyridine-containing macrocycle 2.61 was successfully synthesised and hydrogenated, but was unable to be functionalised with appropriate C-terminal residues due to its poor solubility profile. Chapter three details the design and synthesis of a series of peptidomimetic inhibitors of the serine protease Hip1 which has been implicated with a host innate immune response pathway of Mycobacterium tuberculosis. Described is the synthesis of a library of tripeptides containing an electrophilic boronic ester at the C-terminus for reversible covalent attachment to the Hip1 active site and the associated inhibitory assay data. A lead compound, 3.23, which has exceptional potency of inhibition (low nM activity) was discovered, from which highly potent derivatives featuring a C-terminal aldehyde 3.44, α-keto heterocycle 3.49, and α-keto ester 3.58 were established. Further refinement of these inhibitors presents an opportunity for the development of therapeutics for the treatment of tuberculosis.
Advisor: Abell, Andrew
George, Jonathan
Dissertation Note: Thesis (MPhil) -- University of Adelaide, School of Physical Sciences, 2018
Keywords: Protease
inhibitors
peptidomimetic
serine
cysteine
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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