Automated affinity selection for rapid discovery of peptide binders

Zhang, Genwei; Li, Chengxi; Quartararo, Anthony J.; Loas, Andrei; Pentelute, Bradley L.

doi:10.1039/d1sc02587b

Cited by 19 publications

(17 citation statements)

References 47 publications

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“…AS-MS techniques are another class of promising strategies to address HTS demands of combinatorial libraries. − Large collections of compounds can be rapidly screened, and pharmacologically active hits with potent binding affinity can be isolated by various approaches, including pulsed ultrafiltration, size exclusion chromatography, magnetic beads separation, and the recently developed biolayer interferometry system. , These hits are then identified by powerful mass spectroscopic deconvolution (Figure ). Several lines of evidence show the AS-MS technology to be superior to conventional high-throughput screenings.…”

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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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%

High-Throughput Screening of Stapled Helical Peptides in Drug Discovery

et al. 2022

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“…8,9 Thus, next-generation BLI can be a candidate technology to be incorporated with MS. Efforts were made previously to connect traditional BLI (using optical fiber BLI microprobes instead of quartz-glass ones) with MS, however the two technologies were not directly coupled and the analytes must be eluted before MS analysis. [10][11][12] Because only a tiny amount of analyte (one layer of molecules) could be captured on the surface of a microprobe, the "indirect coupling" required either multiple affinity capture-elution cycles or an additional step of concentration to make up the analyte dilution in elution liquid, resulting in extended experimental procedures.…”

Section: [Hb Paper]mentioning

confidence: 99%

Using Microprobe-Capture In-Emitter Elution to Directly Couple Label-Free Optical Sensing Technology with Mass Spectrometry for Top-Down Protein Analysis

Luo

Yang

2022

Preprint

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Affinity capture of an analyte by a capture agent is one of the most effective sample preparation approaches for protein analytes. We describe a new affinity capture technique for top-down protein analysis, microprobe-capture in-emitter elution (MPIE), which can directly couple a label-free optical sensing technology (next-generation biolayer interferometry, BLI) with MS. In MPIE, an analyte is first captured on the surface of a microprobe while the capture process was monitored in real-time by BLI, and then eluted from the microprobe inside an electrospray emitter. When electrospray is established from the emitter to a mass spectrometer, the analyte is immediately ionized through electrospray ionization (ESI) for MS analysis. By this means, next-generation BLI and MS are directly coupled in the form of MPIE-ESI-MS. The performance of MPIE-ESI-MS was demonstrated by the analysis of Aβ 1-40 and Tf using both standard samples and human specimens. In comparison to the conventional affinity capture techniques such as bead-based immunoprecipitation, MPIE innovated the affinity capture methodology by introducing real-time process monitoring and providing binding characteristics of analytes, providing more information-rich experimental results. Thus, MPIE is a valuable addition to the TD-MS sample preparation toolbox, and more applications of MPIE-ESI-MS in top-down protein analysis can be expected.

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“…Solche kombinatorischen Synthesemethoden gibt es schon seit 30 Jahren, aber erst im Jahr 2020 ermöglichten technische Entwicklungen Affinitätsselektionen mit Bibliotheken in der Größenordnung von Phagen-Display -also etwa eine Milliarde Substanzen. 6) Die Hit-Identitäten werden mit hochempfindlicher Tandem-Mas- zeigten Wirkstoffziele enthalten menschliche krankheitsrelevante Proteine (MDM2 und Menin, die Wirkstoffziele bei verschiedenen Krebsarten sind, und 14-3-3, einem wichtigen regulatorischen Protein), [6][7][8] ein virales Protein (Sars-CoV-2-Spike-receptor binding domain) 9) und eine nicht kodierende Prä-Mikro-RNA (pre-miRNA-21, das in vielen Krebsarten überexprimiert ist). 10) Dies zeigt, wie viele unnatürliche Aminosäuren als Bausteine dienen können.…”

Section: Selbstkodierte Peptidomimetika-bibliothekenunclassified