ArticleCell2022
Accurate de novo design of membrane-traversing macrocycles.
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Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86citing papers in PubMed
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86 citing papers in PubMed.
- Beyond Simple Mimicry: Next-Generation Geometric Architectures and Future Paradigms in Small-Molecule and Macrocyclic Peptidomimetics.Angewandte Chemie (International ed. in English) · 2026Review
- Similarity-Enhanced Representation Learning of Non-Canonical Amino Acids for Therapeutic Peptide Modeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- HighFold4: extending AlphaFold3 to accurate cyclic peptide conformation prediction via custom chemical connectivity.Briefings in bioinformatics · 2026Article
- Article
- Orally available designed miniproteins inhibit enterotoxigenicbioRxiv : the preprint server for biology · 2026Article
- Structure-Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region.ACS medicinal chemistry letters · 2026Article
- Design of permeability-optimized target-binding macrocyclesChemical science · 2026Article
- De novo design of a macrocycle-induced dimerization system for cellular control.Nature communications · 2026Article
- Bridging Heterocycle-Mediated Hydrogen Bonding Facilitates Permeability of Polar Macrobicycles.Journal of the American Chemical Society · 2026Article
- De novo design of a macrocycle induced dimerization system for cellular control.bioRxiv : the preprint server for biology · 2026Article
- Review
- PEGASUS: Unlocking Polarity in Cell-Permeable Cyclic Peptides Using AI Models Built on Massively Parallel Biological Assays.Journal of medicinal chemistry · 2026Article
- Overlooked Complications and Opportunities in the Development of Drugs Based upon Macrobicyclic Peptides: The "Homeomorphic Switch".Journal of the American Chemical Society · 2026Review
- From Cloudy to Clear: A Strategy to Resolve the Complex Structural Elucidation of Bicycle Drug Conjugate Zelenectide Pevedotin by NMR.Bioconjugate chemistry · 2026Article
- Self-assembled nanonetworks of highly stable gemini surfactant-like peptides: antibacterial mechanisms, self-assembly characteristics, and in vivo anti-infection potential.Journal of nanobiotechnology · 2026Article
- Enhancing the Predictive Power of Macrocyclic Drug Permeability by Knowledge Distillation from Analogous Pretraining Data.Journal of medicinal chemistry · 2026Article
- Cyclopeptide 161 protects human dermal fibroblasts against UV-induced damage via the MEK1/2-ERK1/2 signaling pathway.Frontiers in physiology · 2026Article
- Accurate de novo design of high-affinity protein-binding macrocycles using deep learning.Nature chemical biology · 2025Article
- De novo design of light-responsive protein-protein interactions enables reversible formation of protein assemblies.Nature chemistry · 2025Article
- C2PO: an ML-powered optimizer of the membrane permeability of cyclic peptides through chemical modification.Journal of cheminformatics · 2025Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors.
Gaurav BhardwajInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; Biological Physics, Structure and Design program, University of Washington, Seattle, WA 98195, USA. Electronic address: gauravb@uw.edu.
Jacob O'ConnorInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Biological Physics, Structure and Design program, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Stephen RettieInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Molecular Cell and Biology program, University of Washington, Seattle, WA 98195, USA.
Yen-Hua HuangInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
Theresa A RamelotDepartment of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Vikram Khipple MulliganInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Gizem Gokce AlpkilicInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Program, University of Washington, Seattle, WA 98195, USA.
Jonathan PalmerInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Asim K BeraInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Matthew J BickInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Maddalena Di PiazzaInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Xinting LiInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Parisa HosseinzadehInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Timothy W CravenInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Roberto TejeroDepartamento de Quίmica Fίsica, Universidad de Valencia, Avenida Dr. Moliner 50, Burjassot, 46100 Valencia, Spain.
Anna LaukoInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Biological Physics, Structure and Design program, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Ryan ChoiDepartment of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA.
Calina GlynnDepartment of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, USA.
Linlin DongTakeda Pharmaceuticals Inc., Cambridge, MA, USA.
Robert GriffinTakeda Pharmaceuticals Inc., Cambridge, MA, USA.
Wesley C van VoorhisDepartment of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA.
Jose RodriguezDepartment of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, USA.
Lance StewartInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Gaetano T MontelioneDepartment of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
David CraikInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
David BakerInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: dabaker@uw.edu.
Funding
User Training and OutreachP30GM124165 · NIGMS · CORNELL UNIVERSITY · PI STEVEN E EALICK · 2018 to 2026
$34.2MPharmacological Sciences SupplementT32GM007750 · NIGMS · UNIVERSITY OF WASHINGTON · PI ATKINS, WILLIAM M · 1985 to 2023
$12.6MHybrid Methods for Dynamic Structure Analysis of Proteins from Pathogenic MicroorganismsR35GM141818 · NIGMS · RENSSELAER POLYTECHNIC INSTITUTE · PI MONTELIONE, GAETANO T · 2021 to 2025
$3.3MDesigned Vehicles for Blood Brain Barrier TraversalR01AG063845 · NIA · UNIVERSITY OF WASHINGTON · PI BAKER, DAVID · 2019 to 2023
$2.5MMembrane Protein Structure Using Evolutionary Couplings and Sparse NMR DataR01GM120574 · NIGMS · RUTGERS, THE STATE UNIV OF N.J. · PI MONTELIONE, GAETANO T · 2017 to 2020
$2.3MAdvancing genetic code expansion with Rosetta computational design: improving machinery for bioorthogonal amino acidsF32GM120791 · NIGMS · UNIVERSITY OF WASHINGTON · PI HOSSEINZADEH, PARISA · 2016 to 2018
$170kHoward Hughes Medical InstituteNIA NIH HHS R01 AG063845NIGMS NIH HHS F32 GM120791NIGMS NIH HHS P30 GM124165NIGMS NIH HHS R01 GM120574NIGMS NIH HHS R35 GM141818NIGMS NIH HHS T32 GM007750
Abstract
We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10
Indexed as
AmidesPeptidesHydrogenHydrogen BondingLipidsAmidesHydrogenLipidsPeptidescomputational designmembrane permeabilityoral bioavailabilitypeptide design
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