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Effect of C-terminal and N-terminal dimerization and alanine scanning on antibacterial activity of the analogs of the peptide p-BthTX-I
Peptide Science ( IF 1.5 ) Pub Date : 2021-09-16 , DOI: 10.1002/pep2.24243
Norival Alves Santos‐Filho 1 , Gabriela Marinho Righetto 2 , Marina Rodrigues Pereira 1 , Julia Pinto Piccoli 1 , Larissa Mathias Teizen Almeida 1 , Thainá Cristina Leal 1 , Ilana Lopes Baratella Cunha Camargo 2 , Eduardo Maffud Cilli 1
Affiliation  

The peptide (p-BthTX-I)2 [(KKYRYHLKPFCKK)2] and its analog des-Lys12,Lys13-(p-BthTX-I)2 [(KKYRYHLKPFC)2] showed activity against bacteria and potential specificity against prokaryotic cells. In this study, we synthesized the peptide des-Cys11,Lys12,Lys13-(p-BthTX-I)2K [(KKYRYHLKPF)2K] with a Lys instead of a Cys residue in the dimerization step, beginning the SPPS with Fmoc-Lys(Fmoc)-OH. This change avoided Cys oxidation, decreasing one step in the original peptide synthesis and obtaining a smaller and more stable peptide. The antimicrobial activity of the peptide des-Cys11,Lys12,Lys13-(p-BthTX-I)2K was superior to that of the (p-BthTX-I)2 peptide against the bacterial strains tested. Additionally, to evaluate the impact of the linker position on peptide dimerization, we synthesized peptide E(p-BthTX-I)2 [E(KKYRYHLKPFCKK)2] using Fmoc-Glu-OH at the end of the synthesis. This N-terminal dimeric peptide did not increase the antibacterial activity, indicating that the free N-terminal is essential for (p-BthTX-I)2 activity. Additionally, we observed lower antimicrobial activity by substituting positive and aromatic residues with Ala in the alanine scanning assay, irrespective of the amino acid change, indicating that each amino acid is essential for the mechanism of action of the peptide. Therefore, we demonstrated that the (p-BthTX-I)2 analog, which is shorter and synthesized by an easier process leading to a more stable peptide, is the most antibacterial active peptide against multidrug-resistant bacteria and does not increase hemolysis activity.

中文翻译:

C端和N端二聚化和丙氨酸扫描对肽p-BthTX-I类似物抗菌活性的影响

肽 (p-BthTX-I) 2 [(KKYRYHLKPFCKK) 2 ] 及其类似物 des-Lys 12 ,Lys 13 -(p-BthTX-I) 2 [(KKYRYHLKPFC) 2 ] 显示出对细菌的活性和对原核生物的潜在特异性细胞。在这项研究中,我们合成了肽 des-Cys 11 ,Lys 12 ,Lys 13 -(p-BthTX-I) 2 K [(KKYRYHLKPF) 2K] 在二聚化步骤中使用 Lys 而不是 Cys 残基,以 Fmoc-Lys(Fmoc)-OH 开始 SPPS。这一变化避免了 Cys 的氧化,减少了原始肽合成的一个步骤,并获得了更小更稳定的肽。肽des-Cys 11 ,Lys 12 ,Lys 13 -(p-BthTX-I) 2 K 的抗微生物活性优于(p-BthTX-I) 2肽对所测试的细菌菌株的抗微生物活性。此外,为了评估接头位置对肽二聚化的影响,我们合成了肽 E(p-BthTX-I) 2 [E(KKYRYHLKPFCKK) 2] 在合成结束时使用 Fmoc-Glu-OH。这种 N 端二聚肽不增加抗菌活性,表明游离 N 端对 (p-BthTX-I) 2活性至关重要。此外,我们通过在丙氨酸扫描测定中用 Ala 取代阳性和芳香残基观察到较低的抗菌活性,无论氨基酸变化如何,这表明每个氨基酸对于肽的作用机制都是必不可少的。因此,我们证明了 (p-BthTX-I) 2类似物,它更短并且通过更容易的过程合成,从而导致更稳定的肽,是对多重耐药细菌最具抗菌活性的肽,并且不会增加溶血活性。
更新日期:2021-09-16
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