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ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides.

ABSTRACT: ?-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in Alzheimer's disease. Transthyretin is a natural sequestering agent of ?-amyloid oligomers: the binding site to ?-amyloid has been traced to strands G/H of the inner ?-sheet of transthyretin. A linear peptide, with the same primary sequence as the ?-amyloid binding domain on transthyretin, was moderately effective at inhibiting ?-amyloid fibril growth. Insertion of a ?-turn template and cyclization greatly increased stability against proteolysis and improved efficacy as an amyloid inhibitor. However, the cyclic peptide still contained a significant amount of disorder. Using the Simple Cyclic Peptide Application within ROSETTA as an in silico predictor of cyclic peptide conformation and stability, we investigated putative structural enhancements, including stabilization by disulfide linkages and insertion of a second ?-turn template. Several candidates were synthesized and tested for secondary structure and ability to inhibit ?-amyloid aggregation. The results demonstrate that cyclization, ?-sheet structure and conformational homogeneity are all preferable design features, whereas disulfide bond formation across the two ?-strands is not preferable.

SUBMITTER: Est CB

PROVIDER: S-EPMC7212263 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides.

Est Chandler B CB Mangrolia Parth P Murphy Regina M RM

Protein engineering, design & selection : PEDS 20191201 2

β-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in Alzheimer's disease. Transthyretin is a natural sequestering agent of β-amyloid oligomers: the binding site to β-amyloid has been traced to strands G/H of the inner β-sheet of transthyretin. A linear peptide, with the same primary sequence as the β-amyloid binding domain on transthyretin, was moderately effective at inhibiting β-amyloid fibril growth. Insertion of a β-turn template and cyclizatio ...[more]

PMID: 31650164

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Project description:Short antimicrobial peptides are essential to keep us healthy and their lasting potency can inspire the design of new types of antibiotics. This study reports the design of a family of eight-residue tryptophan-rich peptides (TetraF2W) obtained by converting the four phenylalanines in temporin-SHf to tryptophans. The temporin-SHf template was identified from the antimicrobial peptide database (http://aps.unmc.edu/AP). Remarkably, the double arginine variant (TetraF2W-RR) was more effective in killing methicillin-resistant Staphylococcus aureus (MRSA) USA300, but less cytotoxic to human skin HaCat and kidney HEK293 cells, than the lysine-containing dibasic combinations (KR, RK and KK). Killing kinetics and fluorescence spectroscopy suggest membrane targeting of TetraF2W-RR, making it more difficult for bacteria to develop resistance. Because established biofilms on medical devices are difficult to remove, we chose to covalently immobilize TetraF2W-RR onto the polyethylene terephthalate (PET) surface to prevent biofilm formation. The successful surface coating of the peptide is supported by FT-IR and XPS spectroscopies, chemical quantification, and antibacterial assays. This peptide-coated surface indeed prevented S. aureus biofilm formation with no cytotoxicity to human cells. In conclusion, TetraF2W-RR is a short Trp-rich peptide with demonstrated antimicrobial and anti-biofilm potency against MRSA in both the free and immobilized forms. Because these short peptides can be synthesized cost effectively, they may be developed into new antimicrobial agents or used as surface coating compounds.Statement of significanceIt is stunning that the total deaths due to methicillin-resistant Staphylococcus aureus (MRSA) infection are comparable to AIDS/HIV-1, making it urgent to explore new possibilities. This study deals with this problem by two strategies. First, we have designed a family of novel antimicrobial peptides with merely eight amino acids, making it cost effective for chemical synthesis. These peptides are potent against MRSA USA300. Our study uncovers that the high potency of the tryptophan-rich short peptide is coupled with arginines, whereas these Trp- and Arg-rich peptides are less toxic to select human cells than the lysine-containing analogs. Such a combination generates a more selective peptide. As a second strategy, we also demonstrate successful covalent immobilization of this short peptide to the polyethylene terephthalate (PET) surface by first using a chitosan linker, which is easy to obtain. Because biofilms on medical devices are difficult to remove by traditional antibiotics, we also show that the peptide coated surface can prevent biofilm formation. Although rarely demonstrated, we provide evidence that both the free and immobilized peptides target bacterial membranes, rendering it difficult for bacteria to develop resistance. Collectively, the significance of our study is the design of novel antimicrobial peptides provides a useful template for developing novel antimicrobials against MRSA. In addition, orientation-specific immobilization of the same short peptide can prevent biofilm formation on the PET surface, which is widely used in making prosthetic heart valves cuffs and other bio devices.

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ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides.

Publications

ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides.

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