Drug discovery from natural products using affinity selection-mass spectrometry

Muchiri, Ruth N.; Breemen, Richard B. van

doi:10.1016/j.ddtec.2021.10.005

Cited by 9 publications

(7 citation statements)

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“…Meanwhile, a side-by-side analysis of AS-MS with OBOC was recently performed by screening of the same designed peptide library against MDM2 protein, which demonstrated that AS-MS screening inherently prefers to select potent ligands with a narrower range of binding affinities . So far, AS-MS techniques have been successfully used to discover an array of high-quality lead compounds targeting otherwise challenging targets. , Not surprisingly, AS-MS screening of stapled helical peptides is starting to emerge.…”

Section: Identification Of Stapled Helical Peptides By Chemical Combi...mentioning

confidence: 99%

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High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

et al. 2022

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Therapeutic peptides have revolutionized treatment for a number of human diseases. In particular, the past two decades have witnessed rapid progress of stapled helical peptides in drug discovery. Stapled helical peptides are chemically modified and constrained in their bioactive α-helical conformation. Compared to unstabilized linear peptides, stapled helical peptides exhibit superior binding affinity and selectivity, enhanced membrane permeability, and improved metabolic stability, presenting exciting promise for targeting otherwise challenging protein−protein interfaces. In this Perspective, we summarize recent applications of high-throughput screening technologies for identification of potent stapled helical peptides with optimized binding properties. We expect to provide a broad reference to accelerate the development of stapled helical peptides as the next generation of therapeutic peptides for various human diseases.

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Section: Identification Of Stapled Helical Peptides By Chemical Combi...mentioning

confidence: 99%

“…65 So far, AS-MS techniques have been successfully used to discover an array of high-quality lead compounds targeting otherwise challenging targets. 66,67 Not surprisingly, AS-MS screening of stapled helical peptides is starting to emerge.…”

Section: Identification Of Stapled Helical Peptides By Chemical Combi...mentioning

confidence: 99%

High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

et al. 2022

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“…The libraries can consist of ribosomally produced peptides, 9−12 combinatorically prepared synthetic molecules, 13−16 or mixtures of natural compounds. 17 Compared to classical high throughput screenings (HTS), the gold standard in the pharmaceutical industry, AS provides a much faster way to explore a vast chemical space and identify new ligands for drug targets.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Typically, an AS experiment involves mixing a compound library containing millions or even billions of compounds with a target molecule (e.g., a pharmacologically relevant protein) and through a physical separation step, such as protein immobilization, − filtration, or size exclusion chromatography (SEC), − binders from the library are separated from nonbinders. The libraries can consist of ribosomally produced peptides, − combinatorically prepared synthetic molecules, − or mixtures of natural compounds . Compared to classical high throughput screenings (HTS), the gold standard in the pharmaceutical industry, AS provides a much faster way to explore a vast chemical space and identify new ligands for drug targets.…”

Section: Introductionmentioning

confidence: 99%

Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries

Mata,

van der Nol,

Pomplun

2023

J. Am. Chem. Soc.

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Discovering new bioactive molecules is crucial for drug development. Finding a hit compound for a new drug target usually requires screening of millions of molecules. Affinity selection based technologies have revolutionized early hit discovery by enabling the rapid screening of libraries with millions or billions of compounds in short timeframes. In this Perspective, we describe recent technology breakthroughs that enable the screening of ultralarge synthetic peptidomimetic libraries with a barcode-free tandem mass spectrometry decoding strategy. A combination of combinatorial synthesis, affinity selection, automated de novo peptide sequencing algorithms, and advances in mass spectrometry instrumentation now enables hit discovery from synthetic libraries with over 100 million members. We provide a perspective on this powerful technology and showcase success stories featuring the discovery of high affinity binders for a number of drug targets including proteins, nucleic acids, and specific cell types. Further, we show the usage of the technology to discover synthetic peptidomimetics with specific functions and reactivity. We predict that affinity selection coupled with tandem mass spectrometry and automated de novo decoding will rapidly evolve further and become a broadly used drug discovery technology.

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“…Mass spectrometry-based binding assays have been proven capable of quantifying small molecule binding to protein targets without a requirement for compound labeling [20][21][22][23]. In addition, mass spectrometry is a straightforward and accurate method for quantifying ligand concentration.…”

Section: Introductionmentioning

confidence: 99%