Synthesis of cyclotetrapeptide analogues of c-PLAI and evaluation of their antimicrobial properties

Abstract

Antimicrobial peptides (AMPs) are interesting compounds owing to their ability to kill several pathogens. In order to identify new AMPs, c-PLAI analogues were synthesized and evaluated together with their linear precursors for their antimicrobial properties against two Gram-positive bacteria ( Staphylococcus aureus and Bacillus cereus ), two Gram-negative bacteria ( Escherichia coli and Klebsiella pneumoniae ), and two fungal strains ( Candida albicans and Trichophyton mentagrophytes ). The new c-PLAI analogues were prepared through a combination of solid- and solution-phase syntheses, as previously employed for the synthesis of c-PLAI. The antimicrobial activity tests showed that the synthetic parent peptide c-PLAI was inactive or weakly active towards the bioindicators employed in the assay. The tests also indicated that cyclic c-PLAI analogues possessed enhanced antimicrobial properties against most of the bacteria and fungi tested. Furthermore, this study revealed that analogues containing cationic lysine residues displayed the highest activity towards most bioindicators. A combination of lysine and aromatic residues yielded analogues with broad-spectrum antimicrobial properties.

Total synthesis of a reversed cyclopurpuracin using a combination of solid and solution phase methods

“…SPPS was used to synthesize the linear precursor of cyclopurpuracin, which was then cyclized in solution phase. The combination of these methods has been shown to provide cyclopeptides with high purity and yield, as reported by Muhajir et [15], dianthin I synthesis reported by Zhang et al [16] and total synthesis of exumolide A and B reported by Rahmadani et al [17] To obtain a protected-linear precursor, the Fmoc/t-Bu strategy of the orthogonal protecting group was applied in the SPPS. The Fmoc is the protecting group of the α amino group, while t-Bu is the protecting group of the side chain for the serine residue.…”

“…SPPS was used to synthesize the linear precursor of cyclopurpuracin, which was then cyclized in solution phase. The combination of these methods has been shown to provide cyclopeptides with high purity and yield, as reported by Muhajir et al in 2021 in synthesizing Nocardiotide A [13], Kurnia et al in 2022 in synthesizing Xylapeptide B [14], Maharani et al in 2021 in synthesizing c‐PLAI [15], dianthin I synthesis reported by Zhang et al [16] and total synthesis of exumolide A and B reported by Rahmadani et al [17]…”

Total synthesis and antimicrobial evaluation of xylapeptide A

“…The different experimental conditions (different assay systems, different strains, and different growth conditions) could affect the results of the biological activity test [20]. Furthermore, the discrepancy in the activities of the natural versus synthetic peptides may be because synthetic proline-containing cyclopeptides could possess different biological properties despite being chemically similar due to the conformational change in the proline unit [17,[21][22][23]. In addition, there may be differences in the purity between synthetic and natural products.…”

“…Herein, we report the first total synthesis of xylapeptide A by a combination of solid‐ and solution‐phase methods, which have been employed to synthesize several cyclopeptides such as analogues of C‐PLAI [17], nocardiotide A [18], and xylapeptide B [4]. A Fmoc strategy with 2‐chlorotrityl chloride resin as a solid support was used to synthesize the linear precursor of xylapeptide A and a head‐to‐tail cyclization to obtain xylapeptide A in the solution‐phase.…”

Synthesis of a Cyclooctapeptide, Cyclopurpuracin, and Evaluation of Its Antimicrobial Activity

“…In this strategy, a linear precursor is prepared through solid-phase synthesis, while cyclisation is performed in a solution. This method was applied by Muhajir et al in 2021 for the synthesis of nocardiotide A [ 12 ], Kurnia et al in 2022 for the synthesis of xylapeptide B [ 13 ], Maharani et al in 2021 for the synthesis of c-PLAI analogues [ 14 ], Zhang et al in 2016 for the synthesis of dianthin I [ 15 ], and Rahmadani et al in 2021 for the synthesis of exumolide A and B [ 16 ], as well as Yayat et al in 2022 for the synthesis of reversed cyclopurpuracin, as mentioned earlier [ 11 ]. The latter strategy was applied in current studies.…”