ArticleNature chemical biology2019
In-solution enrichment identifies peptide inhibitors of protein-protein interactions.
Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Affinity selection mass spectrometry screening discovers new COP1 peptide binders.RSC chemical biology · 2026Article
- Massive barcode-free chemical screenings enable the discovery of bioactive macrocycles with passive membrane permeability.Nature communications · 2026Article
- Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.Chemical reviews · 2025Review
- The Potential of Peptide-Based Inhibitors in Disrupting Protein-Protein Interactions for Targeted Cancer Therapy.International journal of molecular sciences · 2025Review
- Affinity selection-mass spectrometry with linearizable macrocyclic peptide libraries.Science advances · 2025Article
- Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution.JACS Au · 2024Article
- A Tag-Free Platform for Synthesis and Screening of Cyclic Peptide Libraries.Angewandte Chemie (International ed. in English) · 2024Article
- Development of an α-Klotho Recognizing High-Affinity Peptide Probe from In-Solution Enrichment.JACS Au · 2024Article
- An Update on Protein Kinases as Therapeutic Targets-Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein-Protein Interactions.International journal of molecular sciences · 2023Review
- Advances in Ultrahigh Throughput Hit Discovery with Tandem Mass Spectrometry Encoded Libraries.Journal of the American Chemical Society · 2023Review
- Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer.International journal of biological sciences · 2023Review
- Binary combinatorial scanning reveals potent poly-alanine-substituted inhibitors of protein-protein interactions.Communications chemistry · 2022Article
- Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis.Nature communications · 2022Article
- Accelerated Identification of Cell Active KRAS Inhibitory Macrocyclic Peptides using Mixture Libraries and Automated Ligand Identification System (ALIS) Technology.Journal of medicinal chemistry · 2022Article
- Article
- Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Targeting intracellular protein-protein interactions with macrocyclic peptides.Trends in pharmacological sciences · 2022Review
- High-throughput glycolytic inhibitor discovery targeting glioblastoma by graphite dots-assisted LDI mass spectrometry.Science advances · 2022Article
- A mating mechanism to generate diversity for the Darwinian selection of DNA-encoded synthetic molecules.Nature chemistry · 2022Article
- Rapid de novo discovery of peptidomimetic affinity reagents for human angiotensin converting enzyme 2.Communications chemistry · 2022Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
5 authors.
Funding
Abstract
The use of competitive inhibitors to disrupt protein-protein interactions (PPIs) holds great promise for the treatment of disease. However, the discovery of high-affinity inhibitors can be a challenge. Here we report a platform for improving the affinity of peptide-based PPI inhibitors using non-canonical amino acids. The platform utilizes size exclusion-based enrichment from pools of synthetic peptides (1.5-4 kDa) and liquid chromatography-tandem mass spectrometry-based peptide sequencing to identify high-affinity binders to protein targets, without the need for 'reporter' or 'encoding' tags. Using this approach-which is inherently selective for high-affinity binders-we realized gains in affinity of up to ~100- or ~30-fold for binders to the oncogenic ubiquitin ligase MDM2 or HIV capsid protein C-terminal domain, which inhibit MDM2-p53 interaction or HIV capsid protein C-terminal domain dimerization, respectively. Subsequent macrocyclization of select MDM2 inhibitors rendered them cell permeable and cytotoxic toward cancer cells, demonstrating the utility of the identified compounds as functional PPI inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.