Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753607
Title: Synthesis and biological studies of cyclic peptides
Author: Al-Wafi, Haider
ISNI:       0000 0004 7426 6979
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2018
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Abstract:
Bax peptide 1c (FLIMGWTLD) and two of its derivatives, 15-mer cyclic peptide 2c (FLRELIRTIMGWTLD), 13-mer cyclic peptide 3c (FLKSSKIMGWTLD) with their linear counterparts (1b, 2b, 3b) were prepared by a head−to−tail cyclisation strategy, purified (HPLC), characterised and identified (LCMS). Then the mass and concentration of the two derivatives (2c, 3c) with their linear counterparts (2b, 3b) were calculated. MS2 mass spectra were used as evidence of synthesis of the cyclic peptides from their linear counterparts. There was a clear difference between each of the two cyclic peptides and its linear counterpart’s mass spectra. A peak appeared for a fragment which has the two termini bonded together (Phe−Asp) in the cyclic peptide spectrum (1c, 2c, 3c) that did not appear in the linear peptide spectrum (1b, 2b, 3b). The enzymatic degradation and kinetic study were undertaken for just the two derivatives (2c, 3c) with their linear counterparts (2b, 3b) using trypsin and chymotrypsin. Compound 1c and its linear counterpart (1b) were excluded from these two studies and the stability studies of the peptide in fetal calf serum (FCS) medium because the 9-mer cyclic peptide (1c) had very low solubility in HPLC solvents and was hydrolysed during storage in the freezer. Chymotrypsin cleaved the peptide bond between Trp and Thr but did not cleave the peptide bond between Phe and Asp in the 15-mer cyclic peptide (2c) and its linear counterpart (2b). Cyclisation of the linear peptide (2b) did not improve the stability of the peptide as the t1⁄2 of the cyclic peptide (2c) was less than the t1⁄2 of its linear counterpart (2b). Trypsin cleaved the peptide bond between Arg and Thr in the linear peptide (2b), while in the cyclic peptide (2c) the cleavage was between Arg and Thr in addition to Arg and Glu. Stability of the cyclic peptide (2c) did not improve significantly as the t1⁄2 of compound 2c increased slightly in comparison to the t1⁄2 of its linear counterpart (2b). The effect of chymotrypsin on the two peptides (3b, 3c) was the same. The peptide bond between Trp and Thr was hydrolysed in the two compounds (3b, 3c), while between Phe and Leu did not break. Cyclisation of the linear peptide (3b) did not improve the stability of the peptide because the t1⁄2 of the cyclic peptide (3c) increased slightly in comparison to the t1⁄2 of its linear counterpart (3b). There was significant stability for the cyclic peptide (3c) against trypsin in comparison to its linear counterpart (3b). Compound 3c did not hydrolyse for 30 min, while compound 3b was hydrolysed at the peptide bond between Lys and Ile in the first few minutes of the enzymatic hydrolysis. The stability of 15-mer cyclic compound (2c) was less than its linear counterpart (2b) in the medium of fetal calf serum (FCS) as the t1⁄2 of compound 2c (120 h) was less than the t1⁄2 of compound 2b (165 h). In contrast, the stability of the 13-mer cyclic compound (3c) was more than its linear counterpart (3b) as indicated by the t1⁄2 of compound 3c (285 h) that was more than the t1⁄2 of 3b (110 h).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.753607  DOI: Not available
Keywords: QD Chemistry
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