Dataset Information

Development and Application of Yeast and Phage Display of Diverse Lanthipeptides.

ABSTRACT: Peptide display has enabled identification and optimization of ligands to many targets. These ligands are usually linear or disulfide-containing peptides that are vulnerable to proteolysis or reduction. We report yeast surface and phage display of lanthipeptides, macrocyclic ribosomally synthesized and post-translationally modified peptides (RiPPs). Lanthipeptides contain multiple thioether cross-links that bestow their biological activities. We developed C-terminal yeast display of the class II lanthipeptides lacticin 481 and haloduracin ?, and randomization of the C-ring of the former was used to select tight binders to ?v?3 integrin. This represents the first examples of bacterial RiPP production in Saccharomyces cerevisiae for identification of variants with new biological activities. We also report N-terminal phage display of the class I lanthipeptide nisin and randomization of its A- and B-rings to enrich binders to a small molecule, lipid II. The successful display and randomization of both class I and II lanthipeptides demonstrates the versatility and potential of RiPP display.

SUBMITTER: Hetrick KJ

PROVIDER: S-EPMC5920614 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Development and Application of Yeast and Phage Display of Diverse Lanthipeptides.

Hetrick Kenton J KJ Walker Mark C MC van der Donk Wilfred A WA

ACS central science 20180328 4

Peptide display has enabled identification and optimization of ligands to many targets. These ligands are usually linear or disulfide-containing peptides that are vulnerable to proteolysis or reduction. We report yeast surface and phage display of lanthipeptides, macrocyclic ribosomally synthesized and post-translationally modified peptides (RiPPs). Lanthipeptides contain multiple thioether cross-links that bestow their biological activities. We developed C-terminal yeast display of the class II ...[more]

PMID: 29721528

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Project description:Peptide therapeutics are robust and promising molecules for treating diverse disease conditions. These molecules can be developed from naturally occurring or mimicking native peptides, through rational design and peptide libraries. We developed a new platform for the rapid screening of the peptide therapeutics for disease targets. In the course of the study, we aimed to employ our platform to screen a new generation of peptide therapeutic candidates against aggregation-prone protein targets. Two peptide drug candidates were screened for protein aggregation-prone diseases, namely, Parkinson's and Alzheimer's diseases. Currently, there are several therapeutic applications that are only effective in masking or slowing down symptom development. Nonetheless, different approaches are being developed for inhibiting amyloid aggregation in the secondary nucleation phase, which is critical for amyloid fibril formation. Instead of targeting secondary nucleated protein structures, we tried to inhibit the aggregation of monomeric amyloid units as a novel approach for halting the disease condition. To achieve this, we combined yeast surface display and phage display library platforms. We expressed α-synuclein, amyloid β40, and amyloid β42 on the yeast surface, and we selected peptides by using phage display library. After iterative biopanning cycles optimized for yeast cells, several peptides were selected for interaction studies. All of the peptides have been used for in vitro characterization methods, which are quartz crystal microbalance-dissipation (QCM-D) measurement, atomic force microscopy (AFM) imaging, dot-blotting, and ThT assay, and some of them have yielded promising results in blocking fibrillization. The rest of the peptides, although, interacted with amyloid units which made them usable as a sensor molecule candidate. Therefore, peptides selected by yeast surface display and phage display library combination are good choice for diverse disease-prone molecule inhibition, particularly those inhibiting fibrillization. Additionally, these selected peptides can be used as drugs and sensors to detect diseases quickly and halt disease progression.

Dataset Information

Development and Application of Yeast and Phage Display of Diverse Lanthipeptides.

Publications

Development and Application of Yeast and Phage Display of Diverse Lanthipeptides.

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