High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

Zhang, Yiwei; Guo, Jiabei; Cheng, Jiongjia; Zhang, Zhenghua; Kang, Fenghua; Wu, Xiaoxing; Chu, Qian

doi:10.1021/acs.jmedchem.2c01541

Cited by 9 publications

(10 citation statements)

References 99 publications

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“…However, linear peptides are difficult to pass through cell membranes and are inherently unstable since they undergo proteolysis in cells. To tackle these challenges, chemical modifications of peptides by intramolecular stapling or cyclization have recently emerged as powerful techniques to increase stability, binding affinity, selectivity, and cell permeability of peptides [ 79 , 80 ]. Both techniques can produce conformationally constrained analogs and reduce the entropic cost of binding to IDR targets compared with linear peptides.…”

Section: Utilization Of Antitoxin Idr Dynamics For New Antibiotic Dis...mentioning

confidence: 99%

Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery

Lee

2023

Antibiotics

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Type II toxin-antitoxin (TA) modules are prevalent in prokaryotes and are involved in cell maintenance and survival under harsh environmental conditions, including nutrient deficiency, antibiotic treatment, and human immune responses. Typically, the type II TA system consists of two protein components: a toxin that inhibits an essential cellular process and an antitoxin that neutralizes its toxicity. Antitoxins of type II TA modules typically contain the structured DNA-binding domain responsible for TA transcription repression and an intrinsically disordered region (IDR) at the C-terminus that directly binds to and neutralizes the toxin. Recently accumulated data have suggested that the antitoxin’s IDRs exhibit variable degrees of preexisting helical conformations that stabilize upon binding to the corresponding toxin or operator DNA and function as a central hub in regulatory protein interaction networks of the type II TA system. However, the biological and pathogenic functions of the antitoxin’s IDRs have not been well discussed compared with those of IDRs from the eukaryotic proteome. Here, we focus on the current state of knowledge about the versatile roles of IDRs of type II antitoxins in TA regulation and provide insights into the discovery of new antibiotic candidates that induce toxin activation/reactivation and cell death by modulating the regulatory dynamics or allostery of the antitoxin.

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Section: Utilization Of Antitoxin Idr Dynamics For New Antibiotic Dis...mentioning

confidence: 99%

Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery

Lee

2023

Antibiotics

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“…On the other hand, N-capping with the non-natural motif β HAsp-Pro-Pro enhances the affinity ( K d = 0.062 ± 0.017 μM) without increasing the helical content . Stabilization of the secondary structure is frequently obtained by side chain-to-side chain cyclization, leading to macrocycles often called “stapled peptides”, referring to any short sequence, that has the propensity for α-helical conformation that is constrained by a variety of cross-link synthetic strategies . The simplest one is side chain-to-side chain lactam bridge formation .…”

Section: Introductionmentioning

confidence: 99%

“…28 Stabilization of the secondary structure is frequently obtained by side chain-to-side chain cyclization, leading to macrocycles often called "stapled peptides", referring to any short sequence, that has the propensity for α-helical conformation that is constrained by a variety of cross-link synthetic strategies. 29 The simplest one is side chain-to-side chain lactam bridge formation. 30 Maas et al exploited this reaction to obtain different ACE2(21−55) stapled analogs.…”

Section: ■ Introductionmentioning

confidence: 99%

Antiviral Activity against SARS-CoV-2 of Conformationally Constrained Helical Peptides Derived from Angiotensin-Converting Enzyme 2

et al. 2023

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Despite the availability of vaccines, COVID-19 continues to be aggressive, especially in immunocompromised individuals. Therefore, the development of a specific therapeutic agent with antiviral activity against SARS-CoV-2 is necessary. The infection pathway starts when the receptor binding domain of the viral spike protein interacts with the angiotensin converting enzyme 2 (ACE2), which acts as a host receptor for the RBD expressed on the host cell surface. In this scenario, ACE2 analogs binding to the RBD and preventing the cell entry can be promising antiviral agents. Most of the ACE2 residues involved in the interaction belong to the α1 helix, more specifically to the minimal fragment ACE2(24−42). In order to increase the stability of the secondary structure and thus antiviral activity, we designed different triazole-stapled analogs, changing the position and the number of bridges. The peptide called P3, which has the triazole-containing bridge in the positions 36−40, showed promising antiviral activity at micromolar concentrations assessed by plaque reduction assay. On the other hand, the double-stapled peptide P4 lost the activity, showing that excessive rigidity disfavors the interaction with the RBD.

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“…Stapled peptides have come of age as tool compounds in chemical biology for the regulation of protein‐protein interactions (PPIs) and as lead compounds in drug discovery, with several stapled peptides progressing through clinical trials [1,2] . Conformationally constrained stapled peptides occupy a Goldilocks zone with physicochemical properties between small molecules and biologics.…”

Section: Introductionmentioning

confidence: 99%

Development of Bifunctional, Raman Active Diyne‐Girder Stapled α‐Helical Peptides**

Morgan

McDougall

Knuhtsen

et al. 2023

Chemistry A European J

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Stapled peptides are a unique class of cyclic α‐helical peptides that are conformationally constrained via their amino acid side‐chains. They have been transformative to the field of chemical biology and peptide drug discovery through addressing many of the physicochemical limitations of linear peptides. However, there are several issues with current chemical strategies to produce stapled peptides. For example, two distinct unnatural amino acids are required to synthesize i, i+7 alkene stapled peptides, leading to high production costs. Furthermore, low purified yields are obtained due to cis/trans isomers produced during ring‐closing metathesis macrocyclisation. Here we report the development of a new i, i+7 diyne‐girder stapling strategy that addresses these issues. The asymmetric synthesis of nine unnatural Fmoc‐protected alkyne‐amino acids facilitated a systematic study to determine the optimal (S,S)‐stereochemistry and 14‐carbon diyne‐girder bridge length. Diyne‐girder stapled T‐STAR peptide 29 was demonstrated to have excellent helicity, cell permeability and stability to protease degradation. Finally, we demonstrate that the diyne‐girder constraint is a Raman chromophore with potential use in Raman cell microscopy. Development of this highly effective, bifunctional diyne‐girder stapling strategy leads us to believe that it can be used to produce other stapled peptide probes and therapeutics.

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High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

Cited by 9 publications

References 99 publications

Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery

Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery

Antiviral Activity against SARS-CoV-2 of Conformationally Constrained Helical Peptides Derived from Angiotensin-Converting Enzyme 2

Development of Bifunctional, Raman Active Diyne‐Girder Stapled α‐Helical Peptides**

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