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Backbone Cyclizatio...
Backbone Cyclization and Dimerization of LL-37-Derived Peptides Enhance Antimicrobial Activity and Proteolytic Stability
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- Gunasekera, Sunithi, 1977- (författare)
- Uppsala universitet,Farmakognosi
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- Muhammad, Taj (författare)
- Uppsala universitet,Farmakognosi
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- Strömstedt, Adam A., Dr, 1977- (författare)
- Uppsala universitet,Farmakognosi
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- Rosengren, K. Johan (författare)
- Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia
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- Göransson, Ulf, 1970- (författare)
- Uppsala universitet,Farmakognosi
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(creator_code:org_t)
- 2020-02-21
- 2020
- Engelska.
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; :11
- Relaterad länk:
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https://doi.org/10.3...
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https://uu.diva-port... (primary) (Raw object)
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https://www.frontier...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- Can antimicrobial activity and peptide stability of alpha-helical peptides be increased by making them into dimers and macrocycles? Here, we explore that concept by using KR-12 as the starting point for peptide engineering. KR-12 has previously been determined as the minimalized antimicrobial fragment of the human host defense peptide LL-37. Backbone-cyclized KR-12 dimers, tethered by linkers of two to four amino acid residues, were synthesized and their antimicrobial activity, proteolytic stability and structures characterized. A modified KR-12 sequence, with substitutions at previously identified key residues, were also included in the screening panel. The backbone cyclized KR-12 dimers showed improved antimicrobial activity and increased stability compared to monomeric KR-12. The most active cyclic dimer displayed 16-fold higher antibacterial activity compared to KR-12 against Pseudomonas aeruginosa and Staphylococcus aureus, and 8-fold increased fungicidal activity against Candida albicans. It also showed increased hemolytic and cytotoxic activity. Enhanced antimicrobial activity coincided with increased membrane permeabilization of liposomes with one distinct discrepancy: monomeric KR-12 was much less disruptive of liposomes with bacterial lipid composition compared to liposomes from fungal lipid extract. Circular dichroism showed that the four-residue linked most active cyclic dimer had 65% helical content when bound to lyso-phosphatidylglycerol micelles, indicating that the helical propensity of the parent peptide is maintained in the new macrocyclic form. In conclusion, the current work on KR-12 suggests that dimerization together with backbone cyclization is an effective strategy for improving both potency and stability of linear antimicrobial peptides.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- peptide cyclization
- peptide dimerization
- antimicrobial peptide
- host defense
- KR-12
- LL-37
- Pharmacognosy
- Farmakognosi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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