Accurate de novo design of membrane-traversing macrocycles

Gaurav Bhardwaj; Jacob O'Connor; Stephen Rettie; Yen-Hua Huang; Theresa A Ramelot; Vikram Khipple Mulligan; Gizem Gokce Alpkilic; Jonathan Palmer; Asim K Bera; Matthew J Bick; Maddalena Di Piazza; Xinting Li; Parisa Hosseinzadeh; Timothy W Craven; Roberto Tejero; Anna Lauko; Ryan Choi; Calina Glynn; Linlin Dong; Robert Griffin; Wesley C van Voorhis; Jose Rodriguez; Lance Stewart; Gaetano T Montelione; David Craik; David Baker

doi:10.1016/j.cell.2022.07.019

Accurate de novo design of membrane-traversing macrocycles

Cell. 2022 Sep 15;185(19):3520-3532.e26. doi: 10.1016/j.cell.2022.07.019. Epub 2022 Aug 29.

Authors

Gaurav Bhardwaj¹, Jacob O'Connor², Stephen Rettie³, Yen-Hua Huang⁴, Theresa A Ramelot⁵, Vikram Khipple Mulligan⁶, Gizem Gokce Alpkilic⁷, Jonathan Palmer⁸, Asim K Bera⁶, Matthew J Bick⁶, Maddalena Di Piazza⁸, Xinting Li⁶, Parisa Hosseinzadeh⁶, Timothy W Craven⁹, Roberto Tejero¹⁰, Anna Lauko², Ryan Choi¹¹, Calina Glynn¹², Linlin Dong¹³, Robert Griffin¹³, Wesley C van Voorhis¹¹, Jose Rodriguez¹², Lance Stewart⁶, Gaetano T Montelione⁵, David Craik⁴, David Baker¹⁴

Affiliations

¹ 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.
² 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.
³ Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Molecular Cell and Biology program, University of Washington, Seattle, WA 98195, USA.
⁴ 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.
⁵ Department of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
⁶ Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
⁷ 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.
⁸ Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
⁹ Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
¹⁰ Departamento de Quίmica Fίsica, Universidad de Valencia, Avenida Dr. Moliner 50, Burjassot, 46100 Valencia, Spain.
¹¹ Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA.
¹² Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, USA.
¹³ Takeda Pharmaceuticals Inc., Cambridge, MA, USA.
¹⁴ 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.

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^-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.

Keywords: computational design; membrane permeability; oral bioavailability; peptide design.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides* / chemistry
Hydrogen
Hydrogen Bonding
Lipids
Peptides* / chemistry

Substances

Amides
Lipids
Peptides
Hydrogen

Abstract

Publication types

MeSH terms

Substances

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