De Novo Hydrocarbon-Stapling Design of Single-Turn α-Helical Antimicrobial Peptides

Chen, Zhixia; Yu, Xiuli; Zhang, Aiying; Wang, Fangfang; Xing, Yankun

doi:10.1007/s10989-019-09964-7

Cited by 11 publications

(14 citation statements)

References 52 publications

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“…4a, see SI for detailed characterizations). Consistent with the reported studies that heptapeptides are sufficient in length for stapling and functioning 59,60 , peptides 57-58 retained most of the α-helical folding as shown in CD characterization (Fig. 4b, Table 1).…”

Section: Resultssupporting

confidence: 89%

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

et al. 2022

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We report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of benzenedimethanethiol stapled peptides appeared to be universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways in a distinct pattern in comparison to peptides stapled by RCM. Consistent with the improved cell permeability, the FTDR-stapled lead Axin and p53 peptide analogues demonstrated enhanced inhibition of cancer cells over the RCM-stapled analogues and the unstapled peptides.

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Section: Resultssupporting

confidence: 89%

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

et al. 2022

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“…aureus. Combinations of 1-palmitoyl-2-oleoyl-glycero-3-phosphatidylcholine (POPC) and 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphatidylglycerol, POPC/POPG (7:3) , or 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphatidylethanolamine/POPG (3:1), − lipids were included in these systems. The relationship of these lipid choices to S.…”

Section: Introductionmentioning

confidence: 99%

Generation and Computational Characterization of a Complex Staphylococcus aureus Lipid Bilayer

2022

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Studies indicate a crucial cell membrane role in the antibiotic resistance of Staphylococcus aureus. To simulate its membrane structure and dynamics, a complex molecular-scale computational representation of the S. aureus lipid bilayer was developed. Phospholipid types and their amounts were optimized by reverse Monte Carlo to represent characterization data from the literature, leading to 19 different phospholipid types that combine three headgroups [phosphatidylglycerol, lysyl-phosphatidylglycerol (LPG), and cardiolipin] and 10 tails, including iso- and anteiso-branched saturated chains. The averaged lipid bilayer thickness was 36.7 Å, and area per headgroup was 67.8 Å2. Phosphorus and nitrogen density profiles showed that LPG headgroups tended to be bent and oriented more parallel to the bilayer plane. The water density profile showed that small amounts reached the membrane center. Carbon density profiles indicated hydrophobic interactions for all lipids in the middle of the bilayer. Bond vector order parameters along each tail demonstrated different C–H ordering even within distinct lipids of the same type; however, all tails followed similar trends in average order parameter. These complex simulations further revealed bilayer insights beyond those attainable with monodisperse, unbranched lipids. Longer tails often extended into the opposite leaflet. Carbon at and beyond a branch showed significantly decreased ordering compared to carbon in unbranched tails; this feature arose in every branched lipid. Diverse tail lengths distributed these disordered methyl groups throughout the middle third of the bilayer. Distributions in mobility and ordering reveal diverse properties that cannot be obtained with monodisperse lipids.

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“…Moreover, owing to the vast number of natural peptides with diverse lengths, structures and mechanisms of action, it is difficult to obtain reliable and complete SAR data. Therefore, the de novo design of AMPs based on general structural requirements was applied, and promising data were obtained [ 69 , 73 , 74 ].…”

Section: Diversity Of Antimicrobial Peptidesmentioning

confidence: 99%

Multiple roles of ribosomal antimicrobial peptides in tackling global antimicrobial resistance

et al. 2022

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In the last century, conventional antibiotics have played a significant role in global healthcare. Antibiotics support the body in controlling bacterial infection and simultaneously increase the tendency of drug resistance. Consequently, there is a severe concern regarding the regression of the antibiotic era. Despite the use of antibiotics, host defence systems are vital in fighting infectious diseases. In fact, the expression of ribosomal antimicrobial peptides (AMPs) has been crucial in the evolution of innate host defences and has been irreplaceable to date. Therefore, this valuable source is considered to have great potential in tackling the antimicrobial resistance (AMR) crisis. Furthermore, the possibility of bacterial resistance to AMPs has been intensively investigated. Here, we summarize all aspects related to the multiple applications of ribosomal AMPs and their derivatives in combating AMR.

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De Novo Hydrocarbon-Stapling Design of Single-Turn α-Helical Antimicrobial Peptides

Cited by 11 publications

References 52 publications

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

Generation and Computational Characterization of a Complex Staphylococcus aureus Lipid Bilayer

Multiple roles of ribosomal antimicrobial peptides in tackling global antimicrobial resistance

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