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The design and Synthesis of peptide-inspired antileishmanial agents

CHADBOURNE, FRANCES,LAURA (2014) The design and Synthesis of peptide-inspired antileishmanial agents. Doctoral thesis, Durham University.



Leishmaniasis is a tropical disease caused by protozoan parasite of the genus Leishmania.
The temporins are a class of antimicrobial peptides (AMPs) and have documented antibacterial and antileishmanial activity. Temporins A, B, C, F, L and 1Sa were synthesised. Fluorescein and tetramethylrhodamine, used as biological imaging agents, were attached to temporins A and B and used in biological testing to track the progress of the peptides through infected macrophage cells, and in an in vitro skin model.
Temporins A and L were found to be active against both promastigotes and amastigotes, and alanine and lysine scans of these peptides were performed to attempt to identify any residues causing activity. No residues to this effect were identified, however based on this work, the largest library of antimicrobial peptides to date was synthesised and tested gainst Leishmania mexicana promastigotes and axenic amastigotes. Data obtained was subsequently used in the first reported study of computational modelling to predict the sequences of antileishmanials peptides. Based on this work, peptide sequences were predicted that may show activity as antileishmanials agents.
The Ciliatamides consist of three lipopeptides named Ciliatamides A-C, of which Ciliatamide B was shown to possess high levels of antileishmanial activity. (S,S), (R,S), (S,R) and (R,R) forms of Ciliatamide B were synthesised and used in biological testing.
The activity of both temporins A and B was assayed against L. mexicana promastigote and axenic amastigotes, as well as murine macrophages: Allowing for an as yet undocumented comparison between both stages of the Leishmania spp. lifecyle. Differences were noted in the activity of the promastigotes and amastigotes lifecycle stages of the parasite, with promastigotes being significantly more responsive to AMPs than the amastigotes. As all previous studies had taken place on the promastigotes lifecycle stage, this finding must be taken into consideration in planning future studies.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:Leishmaniasis, peptide
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2014
Copyright:Copyright of this thesis is held by the author
Deposited On:28 May 2014 11:52

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