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Exploring chirality of unnatural amino acids and peptides on water sorption and stratum corneum uptake

Silva Pereira, E. C. (2019) Exploring chirality of unnatural amino acids and peptides on water sorption and stratum corneum uptake. PhD thesis, University of Reading

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Abstract/Summary

Skin is the largest organ in the human body and acts as a protective barrier against exterior chemical and pathogenic agents. Because of the large surface area and easy accessibility, drug delivery through skin has numerous potential applications. The stratum corneum, SC (the outermost layer of the skin), forms the main barrier to diffusion of permeants through the skin; circumventing this barrier is challenging and it is difficult to deliver “large” molecules such as proteins and peptides across the skin. The physicochemical properties of a permeant affect its transport into and through the skin and well characterised diffusional determinants include the octanol/water partition coefficient, molecular weight, solubility and hydrogen bonding groups of a drug. Less well understood is the role of chirality. The enantioselectivity of the skin during epidermal permeation has been poorly researched with few investigations focussing on the effect of drug chirality. In this project, three libraries of unnatural amino acids were synthesised in their racemic and enantiomerically pure forms; a saturated series, an unsaturated series and a hydroxylated series of -amino acids. The monomers were assembled into peptides of different dimensions, specifically dimers, tetramers and in some cases hexamers and octamers. This library was used to probe and seek to understand the effects of increasing molecular weight and chirality on permeant uptake into stratum corneum membranes. In addition, the ability of these materials to hold water, and so act as potential moisturising agents in dry skin conditions was explored. To meet these objectives, the physical properties of these materials were measured and assessed ranging from analytical characterisation (Nuclear Magnetic Resonance - NMR, Mass Spectrometry - MS, Infra-Red - IR) to water uptake assays (Thermal Gravimeric Analysis - TGA, Dynamic Sorption Vapou - DVS). The materials tended to form intramolecular hydrogen bonds as the peptide length increased. Thus, their foldameric structures were also explored using circular dichroism and for some materials with unusual properties X-ray diffraction was performed. Selected compounds were applied to isolated sheets of stratum corneum to assess their uptake. The influence of chirality, molecular weight, chemical composition (saturated, unsaturated and hydroxylated), water holding capacity and secondary structure on the uptake of the material into the tissue were explored and the results illustrated that complex relationships existed between structure and uptake but chiral selectivity of drug uptake into the stratum corneum was demonstrated.

Item Type:Thesis (PhD)
Thesis Supervisor:Williams, A. and Cobb, A.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy
ID Code:85479

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