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Enhancing the Stability of Biologically Active Peptides Apelin and Lactocin S Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
McKinnie, Shaun MK
Supervisor and department
Vederas, John (Chemistry)
Examining committee member and department
Vederas, John (Chemistry)
Yudin, Andrei (Chemistry, University of Toronto)
McMullen, Lynn (Agriculture, Food & Nutritional Science)
Clive, Derrick (Chemistry)
Lowary, Todd (Chemistry)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Peptides have a host of beneficial physiological effects and are often considered for therapeutic application to treat disease. However, poor bioavailabilities, problems with administration, sensitivity to environmental factors, and susceptibility to proteases limit them. The work presented in this thesis highlights efforts towards the chemical synthesis of analogues of two biologically active peptides that have improved stability to their respective limiting factors. An investigation of their improved stability through biological assays will also be used to assess the success of their synthetic modifications. Chapter 2 will discuss antimicrobial lantibiotic lactocin S (26), which rapidly loses its biological activity upon exposure to atmospheric oxygen. The synthesis of a double sulfur-substituted analogue, NleDAP lactocin S (47) will be highlighted along with the antimicrobial testing of this peptide. An assessment of the oxidative stabilities of additional synthetic sulfur-substituted analogues will be done to qualitatively examine the effect of these substitutions on the retention of antimicrobial activity. Chapter 3 will discuss the synthesis of analogues of pyr-1-apelin-13 (71) and apelin-17 (70), peptides with many physiologically significant roles, particularly in the cardiovascular system. However, these peptides are rapidly degraded by plasma proteases in vivo and in vitro. Biochemical evidence to support the significance of angiotensin-converting enzyme 2 (ACE2) in the in vitro degradation of apelin peptides in mouse and human plasma was initially investigated. The synthesis of two unique pyr-1- apelin-13 analogues (103, 104) that showed complete stability to ACE2 and were not inhibitors of this critical regulatory enzyme will be described. Physiological assessments performed by collaborators confirmed that analogue 104 retained full biological activity, and further application of these synthetic modifications to the apelin-17 isoform have resulted in apelin analogues with improved pharmacodynamic properties. The application of ACE2 resistant analogues has enabled the investigation into additional areas of proteolysis of native apelin peptides. Three novel sites of degradation have been identified, along with the proposal of two putative protease candidates believed to be responsible. Lastly, six unique synthetic modifications have been incorporated at one of these cleavage positions, of which Arg4-substituted pyr-1-apelin- 13 analogues show dramatically improved pharmacokinetic stabilities to plasma in vitro. Future physiological testing and structural characterization of these Arg-Leu analogues will give some insight into the proteolysis of this region, as well as the structure-activity relationship of this critical region of the peptide.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Ross, A. C.; McKinnie, S. M. K.; Vederas J. C., The synthesis of active and stable diaminopimelate analogues of the lantibiotic peptide lactocin S. J. Am. Chem. Soc., 2012, 134, 2008-2011.McKinnie, S. M. K.; Ross, A. C.; Little M. J.; Vederas J. C., The solid phase supported peptide synthesis of analogues of the lantibiotic lactocin S. Med. Chem. Commun., 2012, 3, 971-974.Wang, W.; McKinnie, S. M. K.; Patel, V. B.; Haddad, G.; Wang. Z; Zhabyeyev, P.; Das, S. K.; Basu, R.; McLean, B.; Kandalam, V.; Penninger, J. M.; Kassiri, Z.; Vederas, J. C.; Murray, A. G.; Oudit, G. Y., Loss of apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic apelin analogues. J. Am. Heart Assoc., 2013, 2, e000249.

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