The constant problems encountered in the fields of medicinal and pharmaceutical chemistry, especially those related to the side effects of drug candidates, have risen the concern of developing methods that can help us achieve the therapeutic effect without undesired properties. This thesis describes the development of two different Drug Delivery Systems based on the modification of natural occurring molecules. The first one is directed to the treatment of parasitic tropical diseases. The alteration of pantothenic acid with the introduction of a double bond has proved to increase the uptake of fluorescent labelled molecules in different model systems with low cytotoxicity. The concept of this Drug Delivery System relies on the necessity of the parasites to consume the host’s pantothenic acid for their own biological processes. Due to their inability to synthesise this vitamin along with the huge supply they need to survive, it was hypothesised that the increased uptake of CJ-15,801 would allow us to attach interesting molecules that could be selectively delivered into parasites. The second example of a Drug Delivery System presented in this work is based on peptides released by cells of the immune system. The so called Cationic Amphiphilic Peptides are released by an organism that is under the attack of potential pathogens. Due to their physicochemical properties, they can stop an infection by direct killing of microorganisms by different mechanisms. Either by the membrane disruption or internalisation and intracellular targeting, the presence of positively charged residues play a major role on the activity of these peptides. By substitution of the natural occurring lysine and arginine residues with a new class of phosphonium based amino acids, a new class of cationic amphiphilic peptides was synthesised. Fluorescent versions of these peptides have allowed us to investigate their properties. They are characterised by their ability to cross cellular membranes with relatively low toxicity compared to the natural occurring versions of the sequences and even though their direct antimicrobial activity is diminished they can be used as potential Cell Penetrating Peptides. Finally, due to the nature of the cation present in these new peptides, it is theorised that they can have certain selectivity to deliver drugs into mitochondria. Although further studies to prove this need to be done, an initial experiment is reported at the end of this work.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:739227 |
| Date | January 2017 |
| Creators | Silva Nigenda, Ezequiel |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/8917/ |
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