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Mutant lugdunin and their gnp conjugates: syntheses and its application |
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| รหัสดีโอไอ | |
| Title | Mutant lugdunin and their gnp conjugates: syntheses and its application |
| Creator | Nattamon Trirattanaporn |
| Contributor | Panumart Thongyoo, Advisor |
| Publisher | Thammasat University |
| Publication Year | 2566 |
| Keyword | Malaria, Macrocyclic peptide, Lugdunin, Mortiamide, มาลาเรีย, เพปไทด์ที่มีลักษณะเป็นวงขนาดใหญ่ |
| Abstract | The emergence of drug resistant bacteria has now become a serious issue, affecting human health globally. The discovery of novel therapeutic alternatives is urgently necessary. This research represented the exploration of novel strategy to fight against drug resistant bacteria strains by utilizing “Lugdunin” as a promising lead candidate. Lugdunin is a recently isolated novel cyclic peptide, showing highly effective antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). To this work, two synthetic strategies have been proposed; namely (1) the uses of gold nanoparticle (GNPs) conjugation with thiol-incorporated peptides (both linear and cyclic motifs) derived from lugdunin, (2) syntheses of re-engineered mortiamide. Firstly, the design of GNPs-lugdunin conjugates is mainly based on the intrinsic property of GNPs and lugdunin, particularly anti-bacterial activity and its hydrophobic property.Basically, GNPs demonstrated anti-bacterial activity against both gram-positive and gram-negative bacteria and multidrug-resistant strains. To this work, we proposed the functionalization of gold nanoparticles (GNPs) with thiol-incorporated peptides derived from the lugdunin in order to enhance their potentials as anti-microbial agents. Thiol-incorporated peptides were designed based on the lugdunin scaffold, which covalently bonded with GNPs to afford thiol-incorporated peptides-GNP conjugates. Subsequently, thiol-incorporated peptides-GNP conjugates was further analyzed by scanning electron microscopy (SEM), showing the average sizes of 134 and 48 nm of linear and cyclic thiol incorporated peptides-GNPs, respectively. Furthermore, chemical interactions between thiol-incorporated peptides and GNPs via Au-S bond were also confirmed by using infrared and X-ray photoelectron spectroscopy (XPS). To determine the loading capacity, UV-Vis spectroscopy was used to evaluate the loading capacity of a thiol-incorporated peptide-GNPs, showing the loading capacities of approximately 77% and 79% for linear and cyclic thiol- incorporated peptide-GNPs, respectively.The occurrence of drug-resistant plasmodium parasites has caused a significant number of deaths annually. To appropriately address the resistance of plasmodium parasites, there is a critical need for the discovery of new and effective anti-malarial drugs. Herein, we reported the design and syntheses of re-engineered mortiamide peptides based on the combination of mortiamide A and lugdunin scaffold, consisting of seven amino acid residues with linear and cyclic scaffold. Mortiamide A and lugdunin are generally isolated from Mortierella sp. and Staphylococcus lugdunensis, respectively. To this synthetic strategy, the sequence of mortiamide A was partly re-engineered with an epitope sequence of lugdunin together with an amino acid replacement by using L-configuration at Phe1, Val3, Val4, Val5 and Val7 residues. This synthetic approach was carried out via Fmoc based SPPS, giving linear and cyclic re-engineered mortiamides (9-12) in a great yield (>60%). Notably, re-engineered cyclic mortiamide with all-L (11) and D/L configuration (12) showed very promising anti-malarial activities against Plasmodium falciparum sensitive strain (TM4/8) with IC50 values of 6.25±0.52 μM, 4.83±0.10 μM and against Plasmodium falciparum multidrug resistant strain (V1/S) with IC50 values of 5.04±2.60 μM, and 3.75±0.70 μM, respectively. Interestingly, a linear re-engineered mortiamide with D/L configuration (10) not only demonstrated a very potent anti-malarial activity against Plasmodium falciparum sensitive strain (TM4/8) with IC50 value of 3.57±0.52 μM, but it also showed a very promising inhibition against Plasmodium falciparum multidrug resistant strain (V1/S) with an IC50 value of 2.81±0.70 μM with low cytotoxicity (>50 µM). |
