Accurate de novo design of membrane-traversing macrocycles.

Autor:	Bhardwaj G; Institute 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., O'Connor J; Institute 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., Rettie S; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Molecular Cell and Biology program, University of Washington, Seattle, WA 98195, USA., Huang YH; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia., Ramelot TA; Department of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA., Mulligan VK; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Alpkilic GG; Institute 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., Palmer J; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA., Bera AK; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Bick MJ; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Di Piazza M; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA., Li X; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Hosseinzadeh P; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Craven TW; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Tejero R; Departamento de Quίmica Fίsica, Universidad de Valencia, Avenida Dr. Moliner 50, Burjassot, 46100 Valencia, Spain., Lauko A; Institute 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., Choi R; Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA., Glynn C; Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, USA., Dong L; Takeda Pharmaceuticals Inc., Cambridge, MA, USA., Griffin R; Takeda Pharmaceuticals Inc., Cambridge, MA, USA., van Voorhis WC; Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA., Rodriguez J; Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, USA., Stewart L; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Montelione GT; Department of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA., Craik D; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia., Baker D; Institute 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Sep 15; Vol. 185 (19), pp. 3520-3532.e26. Date of Electronic Publication: 2022 Aug 29.
DOI:	10.1016/j.cell.2022.07.019
Abstrakt:	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 -6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics. Competing Interests: Declaration of interests V.K.M. is a cofounder and shareholder of Menten AI, a biotechnology company. G.T.M. is a cofounder of Nexomics Biosciences, Inc., a structural biology contract research organization. A provisional patent covering the membrane-permeable peptides described in this paper has been filed by the University of Washington, Seattle. G.B., L.S., and D.B. are cofounders and shareholders of an early-stage biotechnology company that has licensed the provisional patent. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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