De novo Design of Selective Membrane‐Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface

Shi, Junfeng

doi:10.1002/anie.201902470

Cited by 34 publications

(11 citation statements)

References 42 publications

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“…A prominent difference between iPSCs and differentiated cells is that iPSCs overexpress (or upregulate) alkaline phosphatase (ALP), but the differentiated cells do not. Thus, it is possible to selectively kill iPSCs by using enzyme-instructed self-assembly (EISA), − a molecular process that integrates enzyme reactions and self-assembly and is known to selectively kill cells based on overexpression of enzymes. ,− In fact, Saito et al recently reported selectively eliminating iPSCs by EISA of d -phosphotetrapeptides . Taking the advantage that ALP acts as an ectophosphatase to form pericellular nanofibers of d -peptides, they have shown that ALP overexpressed on iPSCs dephosphorylates the d -phosphotetrapeptides (e.g., 1 ) into hydrophobic peptides, which self-assemble on the cell surface to induce cell death.…”

Section: Introductionmentioning

confidence: 99%

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

et al. 2021

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Tumorigenic risk of undifferentiated human induced pluripotent stem cells (iPSCs), being a major obstacle for clinical application of iPSCs, requires novel approaches for selectively eliminating undifferentiated iPSCs. Here, we show that an l-phosphopentapeptide, upon the dephosphorylation catalyzed by alkaline phosphatase (ALP) overexpressed by iPSCs, rapidly forms intranuclear peptide assemblies made of α-helices to selectively kill iPSCs. The phosphopentapeptide, consisting of four l-leucine residues and a C-terminal l-phosphotyrosine, self-assembles to form micelles/nanoparticles, which transform into peptide nanofibers/nanoribbons after enzymatic dephosphorylation removes the phosphate group from the l-phosphotyrosine. The concentration of ALP and incubation time dictates the morphology of the peptide assemblies. Circular dichroism and FTIR indicate that the l-pentapeptide in the assemblies contains a mixture of an α-helix and aggregated strands. Incubating the l-phosphopentapeptide with human iPSCs results in rapid killing of the iPSCs (=<2 h) due to the significant accumulation of the peptide assemblies in the nuclei of iPSCs. The phosphopentapeptide is innocuous to normal cells (e.g., HEK293 and hematopoietic progenitor cell (HPC)) because normal cells hardly overexpress ALP. Inhibiting ALP, mutating the l-phosphotyrosine from the C-terminal to the middle of the phosphopentapeptides, or replacing l-leucine to d-leucine in the phosphopentapeptide abolishes the intranuclear assemblies of the pentapeptides. Treating the l-phosphopentapeptide with cell lysate of normal cells (e.g., HS-5) confirms the proteolysis of the l-pentapeptide. This work, as the first case of intranuclear assemblies of peptides, not only illustrates the application of enzymatic noncovalent synthesis for selectively targeting nuclei of cells but also may lead to a new way to eliminate other pathological cells that express a high level of certain enzymes.

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Section: Introductionmentioning

confidence: 99%

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

et al. 2021

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“…It has been reported that CPPs could perturb membranes and become membrane permeabilizers at high concentrations, , thus leading to rapid necrosis of cancer cells through membrane lysis . Given the lytic functions of cationic polypeptides, we studied the cytotoxicity effects of drug-free ETCPP dendrimers (Table ).…”

Section: Results and Discussionmentioning

confidence: 99%

Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy

et al. 2022

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Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31–747 nM) against a panel of cancer cells, which is 3–10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.

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“…Published in 2019, Junfeng Shi and Joel Schneider de novo designed a peptide, DVP-1P that is unfolded until it interacts with alkaline phosphatase (ALP), an enzyme that is overexpressed on the surface of some cells including cancer cells [ 95 ]. When the peptide interacts with ALP it causes a conformational shift leading to “cell-surface-induced folding” which can perturb and, in high concentration, lyse the cell membrane.…”

Section: Design Of Protein Interfacesmentioning

confidence: 99%

Recent Progress Using De Novo Design to Study Protein Structure, Design and Binding Interactions

Ferrando

Solomon

2021

Life

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De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context. Since its inception, it has been used to reproduce a plethora of reactions and uncover biophysical principles that are often difficult to extract from direct studies of natural proteins. Natural proteins are capable of assuming a variety of different structures and subsequently binding ligands at impressively high levels of both specificity and affinity. Here, we will review recent examples of de novo design studies on binding reactions for small molecules, nucleic acids, and the formation of protein-protein interactions. We will then discuss some new structural advances in the field. Finally, we will discuss some advancements in computational modeling and design approaches and provide an overview of some modern algorithmic tools being used to design these proteins.

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De novo Design of Selective Membrane‐Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface

Cited by 34 publications

References 42 publications

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy

Recent Progress Using De Novo Design to Study Protein Structure, Design and Binding Interactions

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