Accurate de novo design of membrane-traversing macrocycles.
computational design
membrane permeability
oral bioavailability
peptide design
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
15 09 2022
15 09 2022
Historique:
received:
29
12
2021
revised:
01
05
2022
accepted:
21
07
2022
pubmed:
31
8
2022
medline:
21
9
2022
entrez:
30
8
2022
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 36041435
pii: S0092-8674(22)00922-9
doi: 10.1016/j.cell.2022.07.019
pmc: PMC9490236
pii:
doi:
Substances chimiques
Amides
0
Lipids
0
Peptides
0
Hydrogen
7YNJ3PO35Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3520-3532.e26Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM120574
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007750
Pays : United States
Organisme : NIGMS NIH HHS
ID : F32 GM120791
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG063845
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM141818
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
Références
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17504-9
pubmed: 25416591
Bioinformatics. 2015 Apr 15;31(8):1325-7
pubmed: 25505092
PLoS One. 2012;7(3):e32637
pubmed: 22431978
J Am Chem Soc. 2015 Jan 21;137(2):715-21
pubmed: 25517352
J Am Chem Soc. 2007 Aug 1;129(30):9377-85
pubmed: 17608477
PLoS One. 2011;6(6):e20161
pubmed: 21731610
Medchemcomm. 2012 Oct;3(10):1282-1289
pubmed: 23133740
Science. 2017 Dec 15;358(6369):1461-1466
pubmed: 29242347
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):
pubmed: 33723038
Angew Chem Int Ed Engl. 2018 Sep 10;57(37):11868-11881
pubmed: 29740917
J Pharmacol Toxicol Methods. 2013 Nov-Dec;68(3):334-9
pubmed: 23916595
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
J Mol Biol. 2002 May 24;319(1):209-27
pubmed: 12051947
Chem Rev. 2017 Jun 28;117(12):8094-8128
pubmed: 28541045
ChemMedChem. 2016 May 19;11(10):1048-59
pubmed: 27154275
Mol Pharm. 2011 Apr 4;8(2):479-87
pubmed: 21375270
Nat Chem Biol. 2011 Sep 25;7(11):810-7
pubmed: 21946276
Nat Rev Drug Discov. 2021 Apr;20(4):309-325
pubmed: 33536635
J Mol Biol. 1997 Oct 17;273(1):283-98
pubmed: 9367762
J Appl Crystallogr. 2011 Dec 1;44(Pt 6):1281-1284
pubmed: 22477785
J Comput Chem. 2004 Mar;25(4):510-28
pubmed: 14735570
J Biomol NMR. 1997 Jun;9(4):359-69
pubmed: 9255942
J Biomol NMR. 2001 Nov;21(3):249-61
pubmed: 11775741
J Chem Theory Comput. 2016 Dec 13;12(12):6201-6212
pubmed: 27766851
Acta Crystallogr D Biol Crystallogr. 2001 Jan;57(Pt 1):122-33
pubmed: 11134934
J Phys Chem B. 2018 Mar 1;122(8):2261-2276
pubmed: 29400464
J Biomol NMR. 1995 Nov;6(3):277-93
pubmed: 8520220
Nat Methods. 2009 Aug;6(8):551-2
pubmed: 19644455
Acta Crystallogr A Found Adv. 2015 Jan;71(Pt 1):3-8
pubmed: 25537383
J Med Chem. 2015 Jun 11;58(11):4581-9
pubmed: 25950816
Acta Crystallogr C Struct Chem. 2015 Jan;71(Pt 1):3-8
pubmed: 25567568
Eur J Med Chem. 2003 Mar;38(3):223-32
pubmed: 12667689
ACS Med Chem Lett. 2014 Aug 04;5(10):1148-51
pubmed: 25313329
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
J Am Chem Soc. 2012 Mar 14;134(10):4661-9
pubmed: 22335630
J Chem Theory Comput. 2017 Jun 13;13(6):3031-3048
pubmed: 28430426
Eur J Med Chem. 2015 Jun 5;97:202-13
pubmed: 25974856
Nat Commun. 2021 Jun 7;12(1):3384
pubmed: 34099674
Nature. 2016 Oct 20;538(7625):329-335
pubmed: 27626386
J Biomol NMR. 2013 Aug;56(4):337-51
pubmed: 23897031
J Med Chem. 1998 Mar 26;41(7):1007-10
pubmed: 9544199
J Med Chem. 2017 Mar 9;60(5):1665-1672
pubmed: 28059508
J Am Chem Soc. 2006 Nov 1;128(43):14073-80
pubmed: 17061890
Expert Opin Drug Discov. 2020 Jul;15(7):833-852
pubmed: 32345066
J Biomol NMR. 2015 Sep;63(1):21-37
pubmed: 26123317
Chemistry. 2015 Oct 19;21(43):15148-52
pubmed: 26337831