The Design and Synthesis of Anti-Tubercular Lariatin a Peptidomimetics
| dc.contributor.author | Nyembe, Priscilla Lebohang | |
| dc.contributor.supervisor | Makatini, Maya Mellisa | |
| dc.date.accessioned | 2024-10-14T15:35:05Z | |
| dc.date.available | 2024-10-14T15:35:05Z | |
| dc.date.issued | 2023-07 | |
| dc.description | A dissertation submitted in fulfilment of the requirements for the Degree of Master of Science, to the Faculty of Science, School of Chemistry, University of the Witwatersrand, Johannesburg, 2023. | |
| dc.description.abstract | Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the major causes of death and morbidity worldwide. Approximately 10 million people worldwide are infected with Mtb annually, with an estimated 1.5 million deaths. However, potent anti-TB drugs with a new mechanism of action have not been developed in the last thirty years, and only 5 anti-TB drugs are still clinically used. Currently, available drugs and vaccines have failed to control its spread. Furthermore, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb is a significant public health concern because most of the anti-TB drugs that have been in use for over 40 years are no longer effective for the treatment of these infections. Thus, there is an increased demand for novel anti-tubercular drugs with a different mode of action directed at new Mtb targets. Lariatin A, an anti-mycobacterial peptide, has received interest in the synthesis field due to its distinctive threaded structure which consist of a linear and cyclic portions and its unique bactericidal mechanism toward Mtb. This research focuses on designing and synthesizing derivatives of Lariatin A and investigating their binding properties to the mycobacterium caseinolytic protease (ClpP), a protein essential for the growth of Mtb. A simpler synthetic route for derivatizing Lariatin A peptides was achieved by incorporating two cysteine amino acid residues onto the sequence for cyclization of the peptide via the formation of a disulfide bond instead of a lactam bond. To further simplify the synthetic procedure, derivatives with shorter sequences as well as peptide-peptoids hybrids were also designed. Eight mimetics of Lariatin A were synthesized [Pep_PNL1 (1), Pep_PNL2 (2), Pep_HA (3), Pep_TA (4), Pep_TAA (5), Pep_HAP (6), Pep_PTA (7), Pep_PHA (8)]. The proposed derivatives were synthesized using the solid phase peptide synthesis technique and a sub-monomeric approach was followed to synthesize the peptide-peptoid hybrids. Purification of the peptides was achieved by utilizing semi-preparative High-Pressure Liquid Chromatography and they were characterized by Liquid Chromatography-Mass Spectrometry. The peptides were obtained in low to moderate yields, and the linear tail portion derivative (4) showed 70% ClpP inhibition, while the linear tail derivative coupled to the adamantane moiety (5) showed a 49% inhibition factor. NMR (nuclear magnetic resonance spectroscopy) and CD (circular dichroism) were utilized to determine the secondary structural features. The CD experiments indicated that peptide 1 adopts stable conformations while its separate tail (4) and cyclic (3) regions loss conformity. Pep_PTA (7) displayed the characteristics of both peptide and peptoid as seen from its formation of beta sheets. NMR and CD experiments confirmed that 4 exist in a helical conformation. Hence helical Lariatin A derivatives targeting the Mycobacterium tuberculosis caseinolytic protease can be synthesized using the solid phase peptide synthesis strategy. | |
| dc.description.sponsorship | National Research Foundation (NRF). | |
| dc.description.submitter | MM2024 | |
| dc.faculty | Faculty of Science | |
| dc.identifier | 0000-0002-9819-4506 | |
| dc.identifier.citation | Nyembe, Priscilla Lebohang. (2023). The Design and Synthesis of Anti-Tubercular Lariatin a Peptidomimetics. [Master's dissertation, University of the Witwatersrand, Johannesburg]. https://hdl.handle.net/10539/41578 | |
| dc.identifier.uri | https://hdl.handle.net/10539/41578 | |
| dc.language.iso | en | |
| dc.publisher | University of the Witwatersrand, Johannesburg | |
| dc.rights | ©2023 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg. | |
| dc.rights.holder | University of the Witwatersrand, Johannesburg | |
| dc.school | School of Chemistry | |
| dc.subject | Lariatin A | |
| dc.subject | Antimicrobial peptides | |
| dc.subject | Peptoids | |
| dc.subject | Lasso peptides | |
| dc.subject | Cyclic peptides | |
| dc.subject | Peptidomimetics | |
| dc.subject | Anti-tubercular | |
| dc.subject | UCTD | |
| dc.subject.other | SDG-3: Good health and well-being | |
| dc.title | The Design and Synthesis of Anti-Tubercular Lariatin a Peptidomimetics | |
| dc.type | Dissertation |