Graham, Ben (2019) The rational design and synthesis of novel antifreeze(glyco)protein biomimetics for biomedical applications. PhD thesis, University of Warwick.

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Abstract

The cryopreservation and storage of biological materials essential to biomedicine – such as blood, stem cells, and tissues – is hampered by poor cellular recoveries and viabilities. This is largely due to the formation of ice crystals during the freeze/thaw process, causing catastrophic ice induced damage to cell-based material. Without a reliable, reproducible, and effective cryopreservation method, it is not possible to maintain an on-demand, high quality, and ready supply of vital, life-saving biological products – impacting upon both lives and biomedical research and development. Strategies to inhibit this ice induced damage would therefore have wide application in biomedicine.

Many organisms inhabiting sub-zero environments are able to survive and thrive without issue. Shrubs, plants, insects, but particularly, marine life, have all demonstrated varying degrees of ‘cold protection’. Antifreeze glycoproteins (AFGPs) found in cold water fish, are known to infer substantial protection on these cold-dwelling organisms, where surrounding water temperatures are typically –2 ºC, and yet, the fish don’t freeze solid. AFGPs have been shown to prevent ice crystal growth, and whilst cytotoxic, mimics of AFGPs may have translational application in the cryopreservation of biological materials.

This thesis reports on a series of proof-of-concept studies, intending to replicate the fundamental cryoprotective properties of AFGPs on simple synthetic constructs, so that they may be applied to cryopreservation. This study intends to further elucidate the precise engineering required to incorporate potent ice growth inhibitory properties into a synthetic architecture. By establishing fundamental design rules, a ‘blueprint’ maybe prepared for the future development of potent ice recrystallisation inhibitors, with applications in improving biological storage. Chapter 1 provides a comprehensive literature study of the pre-existing field, whilst Chapter 2 reports on the development of poly(proline) as a potential ice growth inhibitor, mirroring the same solution structure and amphipathic balance as AFGP as core design motifs. Chapter 3 outlines the synthesis of a photo-activatable ice growth inhibitors with potential applications in cryosurgery, representing a tuneable AFGP mimetic.

Drawing further on the apparent design features and properties of AFGP, Chapter 4 details the de novo design of a library of facially amphipathic and rigid AFGP mimetics, which are capable of potently inhibiting ice crystal growth. Chapter 5 reports on the attempted development of a series of bile acid derivatives, featuring the core design motifs associated with AFGPs; domain rigidity/facial amphipathy, helicity, and flexibility.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Antifreeze proteins, Biomimetics, Glycoproteins -- Synthesis
Official Date:	June 2019
Dates:	Date Event June 2019 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Gibson, Matthew I.
Sponsors:	European Research Council ; Royal Society of Chemistry (Great Britain) ; Society of Chemical Industry (Great Britain)
Extent:	xxviii, 281 leaves [8 leaves] : illustrations, charts
Language:	eng

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