Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I.
chemoenzymatic synthesis
chemoproteomics
covalent inhibitor
natural product
proteasome
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
22
04
2020
revised:
22
05
2020
accepted:
17
07
2020
pubmed:
9
8
2020
medline:
7
7
2021
entrez:
9
8
2020
Statut:
ppublish
Résumé
The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I toward the β2 and β5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I.
Identifiants
pubmed: 32763140
pii: S2451-9456(20)30285-3
doi: 10.1016/j.chembiol.2020.07.012
pmc: PMC8201661
mid: NIHMS1700509
pii:
doi:
Substances chimiques
Peptides, Cyclic
0
Proteasome Inhibitors
0
cepafungin I
130743-08-7
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1318-1326.e18Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM128895
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests A.Amatuni, A.S., A.Adibekian, and H.R. have applied for a provisional patent for this work.
Références
Cancer Res. 2005 Sep 1;65(17):7896-901
pubmed: 16140960
Org Lett. 2010 May 21;12(10):2402-5
pubmed: 20426399
J Biol Chem. 2005 Mar 25;280(12):11840-50
pubmed: 15661736
Nat Methods. 2005 May;2(5):357-62
pubmed: 15846363
Bio Protoc. 2014 Jan 20;4(2):
pubmed: 27441204
Angew Chem Int Ed Engl. 2013 May 10;52(20):5271-4
pubmed: 23592388
Angew Chem Int Ed Engl. 2015 Sep 7;54(37):10852-7
pubmed: 26211368
J Biol Chem. 2003 Oct 17;278(42):41528-34
pubmed: 12909627
Exp Cell Res. 2015 Jul 1;335(1):12-22
pubmed: 25882495
Nat Rev Cancer. 2004 May;4(5):349-60
pubmed: 15122206
Chem Biol. 2010 Oct 29;17(10):1077-83
pubmed: 21035730
J Org Chem. 2018 Jun 15;83(12):6741-6747
pubmed: 29798667
Nat Rev Clin Oncol. 2017 Jul;14(7):417-433
pubmed: 28117417
Structure. 2006 Mar;14(3):451-6
pubmed: 16531229
Biochem Biophys Res Commun. 2019 Sep 17;517(2):188-192
pubmed: 31327494
Org Lett. 2010 Aug 6;12(15):3453-5
pubmed: 20597471
Chem Sci. 2017 Oct 1;8(10):6959-6963
pubmed: 29147522
Oncotarget. 2016 Sep 13;7(37):59727-59741
pubmed: 27487129
Angew Chem Int Ed Engl. 2014 May 5;53(19):4836-9
pubmed: 24668894
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18367-71
pubmed: 23091006
Proteomics. 2017 Apr;17(7):
pubmed: 27709814
Chem Commun (Camb). 2011 Jan 7;47(1):385-7
pubmed: 20830349
Angew Chem Int Ed Engl. 2018 Apr 23;57(18):5037-5041
pubmed: 29481729
Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6507-12
pubmed: 19359491
J Antibiot (Tokyo). 1988 Oct;41(10):1338-50
pubmed: 3142841
Cancer Res. 2001 Apr 1;61(7):3071-6
pubmed: 11306489
J Org Chem. 2004 Jan 9;69(1):130-41
pubmed: 14703388
Int J Pept Protein Res. 1985 Sep;26(3):236-41
pubmed: 3902691
Cell Chem Biol. 2019 Mar 21;26(3):340-351.e3
pubmed: 30612952
J Am Chem Soc. 2005 Dec 7;127(48):16912-20
pubmed: 16316237
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Chem Biol. 2009 Dec 24;16(12):1278-89
pubmed: 20064438
Mol Biol Cell. 2002 May;13(5):1536-49
pubmed: 12006651
J Antibiot (Tokyo). 1990 Jul;43(7):783-7
pubmed: 2387772
Cell Cycle. 2014;13(14):2248-61
pubmed: 24875404
ACS Cent Sci. 2020 Feb 26;6(2):241-246
pubmed: 32123742
Expert Rev Proteomics. 2018 Dec;15(12):1033-1052
pubmed: 30427223
J Antibiot (Tokyo). 1988 Dec;41(12):1812-22
pubmed: 3145257
J Antibiot (Tokyo). 1988 Oct;41(10):1331-7
pubmed: 3142840
FEBS Lett. 2009 Jan 22;583(2):401-6
pubmed: 19111544
Sci Rep. 2019 Aug 27;9(1):12418
pubmed: 31455793
Phys Chem Chem Phys. 2014 May 28;16(20):9422-31
pubmed: 24722729
Angew Chem Int Ed Engl. 2019 Aug 19;58(34):11657-11660
pubmed: 31241812
J Org Chem. 2010 Jul 16;75(14):4657-73
pubmed: 20540516
Org Biomol Chem. 2019 Feb 13;17(7):1736-1739
pubmed: 30320324
Mol Cell Biol. 2007 May;27(10):3667-81
pubmed: 17339342
Cancer Res. 1993 Sep 1;53(17):3976-85
pubmed: 8358726
Nat Methods. 2013 Jul;10(7):634-7
pubmed: 23749302
Blood. 2007 Nov 1;110(9):3281-90
pubmed: 17591945
Blood Cancer J. 2016 Jul 15;6(7):e446
pubmed: 27421095
Org Lett. 2016 May 6;18(9):2312-5
pubmed: 27123978
Chem Biol. 2004 Apr;11(4):535-46
pubmed: 15123248
Biochemistry. 2012 Aug 28;51(34):6880-8
pubmed: 22870914
Biochem Pharmacol. 2007 Aug 15;74(4):557-65
pubmed: 17606223
Nat Prod Rep. 2011 Oct;28(11):1854-67
pubmed: 21904761
Cell Chem Biol. 2017 Feb 16;24(2):218-230
pubmed: 28132893
J Neurochem. 2005 Aug;94(4):943-56
pubmed: 15992382
Blood. 2008 Sep 15;112(6):2489-99
pubmed: 18565852
Bioorg Med Chem Lett. 2011 Jan 1;21(1):358-62
pubmed: 21112780
Nature. 2008 Apr 10;452(7188):755-8
pubmed: 18401409