Targeted β‐catenin ubiquitination and degradation by multifunctional stapled peptides

2021 ◽  
Author(s):  
Xiaofeng Wang ◽  
Liuli Dong ◽  
Jiongjia Cheng ◽  
Gregory L. Verdine ◽  
Aijun Lin ◽  
...  
Keyword(s):  
Stapled Peptides

scholarly journals Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 721
Author(s):  
Srinivasaraghavan Kannan ◽  
Pietro G. A. Aronica ◽  
Thanh Binh Nguyen ◽  
Jianguo Li ◽  
Chandra S. Verma
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Diagnostic Tools ◽  
Stapled Peptides ◽  
Altered Expression ◽  
Cellular Processes ◽  
High Affinity ◽  
Limited Success ◽  
Dynamics Simulations ◽  
Partner Proteins

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics.

scholarly journals Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress

2014 ◽  
Vol 57 (15) ◽  
pp. 6275-6288 ◽  
Author(s):  
Loren D. Walensky ◽  
Gregory H. Bird
Keyword(s):  
Stapled Peptides

Stapled Peptides Targeting SARS-CoV-2 Spike Protein HR1 Inhibit the Fusion of Virus to Its Cell Receptor

2021 ◽  
Author(s):  
Mengjun Zheng ◽  
Wei Cong ◽  
Haoran Peng ◽  
Jie Qing ◽  
Huaxing Shen ◽  
...  
Keyword(s):  
Cell Receptor ◽  
Spike Protein ◽  
Stapled Peptides

Late-Stage Diversification through Manganese-Catalyzed C−H Activation: Access to Acyclic, Hybrid, and Stapled Peptides

2019 ◽  
Vol 131 (11) ◽  
pp. 3514-3518 ◽  
Author(s):  
Nikolaos Kaplaneris ◽  
Torben Rogge ◽  
Rongxin Yin ◽  
Hui Wang ◽  
Giedre Sirvinskaite ◽  
...  
Keyword(s):  
Late Stage ◽  
Stapled Peptides

Late‐Stage Peptide Diversification through Cobalt‐Catalyzed C−H Activation: Sequential Multicatalysis for Stapled Peptides

2019 ◽  
Vol 58 (6) ◽  
pp. 1684-1688 ◽  
Author(s):  
Mélanie M. Lorion ◽  
Nikolaos Kaplaneris ◽  
Jongwoo Son ◽  
Rositha Kuniyil ◽  
Lutz Ackermann
Keyword(s):  
Late Stage ◽  
Stapled Peptides

Stapled Peptides as Anti-Apoptotic Drugs

2012 ◽  
Vol 01 (03) ◽  
Author(s):  
Gary L. Johanning
Keyword(s):  
Stapled Peptides

scholarly journals HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

2018 ◽  
Author(s):  
Angela Steinauer ◽  
Jonathan R. LaRochelle ◽  
Rebecca Wissner ◽  
Samuel Berry ◽  
Alanna Schepartz
Keyword(s):  
Cell Penetrating Peptides ◽  
Correlation Spectroscopy ◽  
Confocal Imaging ◽  
Endocytic Pathway ◽  
Endosomal Escape ◽  
Stapled Peptides ◽  
Critical Determinant ◽  
Small Proteins ◽  
Primary Means ◽  
The Difference

AbstractProtein therapeutics represent a significant and growing component of the modern pharmacopeia, but their potential to treat human disease is limited because most proteins fail to traffic across biological membranes. Recently, we discovered that cell-permeant miniature proteins (CPMPs) containing a precisely defined, penta-arginine motif traffic readily to the cytosol and nucleus with efficiencies that rival those of hydrocarbon-stapled peptides active in animals and man. Like many cell-penetrating peptides (CPPs), CPMPs enter the endocytic pathway; the difference is that CPMPs are released efficiently from endosomes while other CPPs are not. Here, we seek to understand how CPMPs traffic from endosomes into the cytosol and what factors contribute to the efficiency of endosomal release. First, using two complementary cell-based assays, we exclude endosomal rupture as the primary means of endosomal escape. Next, using a broad spectrum of techniques, including an RNA interference (RNAi) screen, fluorescence correlation spectroscopy (FCS), and confocal imaging, we identify VPS39—a gene encoding a subunit of the homotypic fusion and protein sorting (HOPS) complex—as a critical determinant in the trafficking of CPMPs and hydrocarbon-stapled peptides to the cytosol. Although CPMPs neither inhibit nor activate HOPS function, HOPS activity is essential to efficiently deliver CPMPs to the cytosol. Subsequent multi-color confocal imaging studies identify CPMPs within the endosomal lumen, particularly within the intraluminal vesicles (ILVs) of Rab7+ and Lamp1+ endosomes that are the products of HOPS-mediated fusion. These results suggest that CPMPs require HOPS to reach ILVs—an environment that serves as a prerequisite for efficient endosomal escape.

CHAPTER 8. Double-click Stapled Peptides for Inhibiting Protein–Protein Interactions

2017 ◽  
pp. 164-187 ◽  
Author(s):  
K. Sharma ◽  
D. L. Kunciw ◽  
W. Xu ◽  
M. M. Wiedmann ◽  
Y. Wu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Stapled Peptides ◽  
Inhibiting Protein

scholarly journals Stapled Peptides—A Useful Improvement for Peptide-Based Drugs

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3654 ◽  
Author(s):  
Mattia Moiola ◽  
Misal G. Memeo ◽  
Paolo Quadrelli
Keyword(s):  
Amino Acids ◽  
Scientific Community ◽  
Peptide Structure ◽  
Peptide Drug ◽  
Cross Link ◽  
Stapled Peptides ◽  
New Techniques ◽  
Low Degree ◽  
Drug Synthesis ◽  
The Right

Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an α -helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis.

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