Inhibitors of SARS-CoV-2 PLpro.
COVID-19
GRL-0617
Nsp3
SARS-CoV-2
antiviral drug discovery
medicinal chemistry
papain like protease (PLpro)
structure-activity relationship (SAR)
Journal
Frontiers in chemistry
ISSN: 2296-2646
Titre abrégé: Front Chem
Pays: Switzerland
ID NLM: 101627988
Informations de publication
Date de publication:
2022
2022
Historique:
received:
15
02
2022
accepted:
28
03
2022
entrez:
13
5
2022
pubmed:
14
5
2022
medline:
14
5
2022
Statut:
epublish
Résumé
The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.
Identifiants
pubmed: 35559224
doi: 10.3389/fchem.2022.876212
pii: 876212
pmc: PMC9086436
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
876212Informations de copyright
Copyright © 2022 Calleja, Lessene and Komander.
Déclaration de conflit d'intérêts
DK serves on the SAB of BioTheryX Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Viruses. 2019 Apr 04;11(4):
pubmed: 30987343
Sci Transl Med. 2021 Sep 22;13(612):eabd5524
pubmed: 34550729
Annu Rev Virol. 2015 Nov;2(1):265-88
pubmed: 26958916
Curr Med Chem. 2021;28(11):2218-2233
pubmed: 32900342
Cell Chem Biol. 2022 May 19;29(5):774-784.e8
pubmed: 35021060
Nature. 2020 Mar;579(7798):270-273
pubmed: 32015507
FEBS J. 2014 Sep;281(18):4085-96
pubmed: 25039866
N Engl J Med. 2021 Feb 11;384(6):497-511
pubmed: 33264556
Lancet. 2020 Feb 22;395(10224):565-574
pubmed: 32007145
Acta Pharm Sin B. 2020 May;10(5):766-788
pubmed: 32292689
N Engl J Med. 2003 May 15;348(20):1953-66
pubmed: 12690092
JAMA. 2020 Sep 15;324(11):1048-1057
pubmed: 32821939
Front Pharmacol. 2021 Aug 17;12:702472
pubmed: 34483904
J Med Chem. 2010 Apr 8;53(7):2719-40
pubmed: 20131845
Nat Commun. 2021 Feb 2;12(1):743
pubmed: 33531496
ChemMedChem. 2021 Jan 19;16(2):340-354
pubmed: 32930481
J Infect Dis. 2021 Aug 2;224(3):415-419
pubmed: 33961695
ACS Infect Dis. 2020 Aug 14;6(8):2099-2109
pubmed: 32428392
J Med Chem. 2010 Jul 8;53(13):4968-79
pubmed: 20527968
Sci Rep. 2021 Feb 11;11(1):3640
pubmed: 33574416
ACS Chem Biol. 2014 Oct 17;9(10):2366-73
pubmed: 25089658
Nature. 2017 Oct 26;550(7677):481-486
pubmed: 29045389
N Engl J Med. 2020 Feb 20;382(8):727-733
pubmed: 31978945
Eur J Med Chem. 2019 Jan 1;161:252-276
pubmed: 30366253
SLAS Discov. 2020 Dec;25(10):1152-1161
pubmed: 33043784
J Biol Chem. 2021 Jul;297(1):100770
pubmed: 33989635
Front Mol Biosci. 2020 Dec 04;7:616341
pubmed: 33344509
J Biomol Struct Dyn. 2021 Sep;39(14):5129-5136
pubmed: 32597315
Cell. 2020 May 14;181(4):914-921.e10
pubmed: 32330414
J Biol Chem. 2004 Jan 16;279(3):1637-42
pubmed: 14561748
Nucleic Acids Res. 2017 Jan 9;45(1):198-205
pubmed: 27694309
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-5
pubmed: 19805192
Am J Gastroenterol. 2020 Oct;115(10):1617-1623
pubmed: 32852338
J Med Chem. 2009 Aug 27;52(16):5228-40
pubmed: 19645480
Front Pharmacol. 2021 Jan 25;11:592737
pubmed: 33708112
Sci Transl Med. 2017 Jun 28;9(396):
pubmed: 28659436
J Virol. 2004 Dec;78(24):13600-12
pubmed: 15564471
Nat Med. 2020 Apr;26(4):450-452
pubmed: 32284615
Antiviral Res. 2019 Sep;169:104541
pubmed: 31233808
J Am Chem Soc. 2019 Mar 20;141(11):4526-4530
pubmed: 30821975
Biochem J. 2021 Jul 16;478(13):2517-2531
pubmed: 34198325
ACS Cent Sci. 2021 Jul 28;7(7):1245-1260
pubmed: 34341772
N Engl J Med. 2022 Feb 10;386(6):509-520
pubmed: 34914868
Antiviral Res. 2015 Mar;115:21-38
pubmed: 25554382
ACS Cent Sci. 2020 May 27;6(5):672-683
pubmed: 32483554
Nat Rev Microbiol. 2021 Mar;19(3):155-170
pubmed: 33116300
J Med Chem. 2022 Jan 13;65(1):876-884
pubmed: 34981929
Proc Natl Acad Sci U S A. 1967 Apr;57(4):933-40
pubmed: 5231356
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5717-22
pubmed: 16581910
iScience. 2021 Oct 22;24(10):103213
pubmed: 34632326
Chem Sci. 2020 Sep 1;11(36):9904-9909
pubmed: 34094251
Sci Rep. 2017 Nov 2;7(1):14978
pubmed: 29097800
J Med Chem. 2014 Mar 27;57(6):2393-412
pubmed: 24568342
Nature. 2021 Dec 13;:
pubmed: 34903873
N Engl J Med. 2003 May 15;348(20):1967-76
pubmed: 12690091
Front Microbiol. 2021 Jul 14;12:682603
pubmed: 34335504
Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0268020
pubmed: 34097489
ACS Chem Biol. 2015 Jun 19;10(6):1456-65
pubmed: 25746232
Bioorg Med Chem. 2018 Jun 1;26(10):2700-2707
pubmed: 28720325
Bioorg Med Chem. 2012 Oct 1;20(19):5928-35
pubmed: 22884354
N Engl J Med. 2020 Nov 5;383(19):1827-1837
pubmed: 32459919
Acta Pharm Sin B. 2021 Jan;11(1):237-245
pubmed: 32895623
Nature. 2020 Nov;587(7835):657-662
pubmed: 32726803
Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10750-10755
pubmed: 30282735
Sci Transl Med. 2020 Apr 29;12(541):
pubmed: 32253226
Sci Rep. 2021 Mar 8;11(1):5433
pubmed: 33686143
Anal Biochem. 2007 Dec 15;371(2):201-7
pubmed: 17869210
Nat Rev Drug Discov. 2017 Aug;16(8):531-543
pubmed: 28685762
Protein Cell. 2021 Nov;12(11):877-888
pubmed: 33864621
Biochemistry. 1998 Feb 17;37(7):1868-79
pubmed: 9485312
Annu Rev Biochem. 2017 Jun 20;86:159-192
pubmed: 28498721
Cell Death Differ. 2021 Feb;28(2):570-590
pubmed: 33414510
mBio. 2018 Mar 6;9(2):
pubmed: 29511076
Int J Biol Macromol. 2021 Oct 1;188:137-146
pubmed: 34364941
Front Pharmacol. 2021 Jan 14;11:611087
pubmed: 33597880
Front Chem. 2021 Mar 12;9:622898
pubmed: 33889562
Biomolecules. 2021 May 28;11(6):
pubmed: 34071582
Nat Commun. 2021 May 24;12(1):3061
pubmed: 34031399
JAMA. 2020 Feb 25;323(8):707-708
pubmed: 31971553
Cell. 2021 Sep 16;184(19):4848-4856
pubmed: 34480864
J Med Chem. 2022 Feb 24;65(4):2940-2955
pubmed: 34665619
ChemMedChem. 2020 Jun 4;15(11):907-932
pubmed: 32324951
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
pubmed: 16381955
Curr Opin Chem Biol. 2011 Feb;15(1):174-82
pubmed: 21075044
Front Pharmacol. 2021 Aug 11;12:700703
pubmed: 34456726
Mol Cell. 2016 May 19;62(4):572-85
pubmed: 27203180
ACS Pharmacol Transl Sci. 2022 Jan 24;5(2):102-109
pubmed: 35178512
Mol Divers. 2022 Feb;26(1):215-228
pubmed: 33675510
J Biol Chem. 2020 Sep 11;295(37):12910-12934
pubmed: 32661197
Science. 2021 Dec 24;374(6575):1586-1593
pubmed: 34726479
Antiviral Res. 2014 Jan;101:122-30
pubmed: 24269475
Nature. 2016 Mar 17;531(7594):381-5
pubmed: 26934220
mBio. 2012 Nov 20;3(6):
pubmed: 23170002
Nat Microbiol. 2021 Jan;6(1):11-18
pubmed: 33273742
Oncogene. 2012 May 10;31(19):2373-88
pubmed: 21996736
J Virol. 2005 Dec;79(24):15189-98
pubmed: 16306590
Nature. 2021 Oct 8;:
pubmed: 34625735
J Virol. 2020 Oct 27;94(22):
pubmed: 32843534
Nat Rev Mol Cell Biol. 2022 Jan;23(1):21-39
pubmed: 34824452
Blood. 2017 Aug 3;130(5):655-665
pubmed: 28576876
Viruses. 2020 Jun 30;12(7):
pubmed: 32629804
Sci Transl Med. 2022 Jan 19;14(628):eabl7430
pubmed: 34941423
Nat Med. 2004 Apr;10(4):368-73
pubmed: 15034574
J Virol. 2005 Jan;79(2):884-95
pubmed: 15613317
Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16119-24
pubmed: 18852458
Cell Rep. 2021 May 18;35(7):109133
pubmed: 33984267
J Med Chem. 2020 Mar 26;63(6):2731-2750
pubmed: 31682427
EMBO J. 2020 Sep 15;39(18):e106275
pubmed: 32845033
Cell Chem Biol. 2021 Jun 17;28(6):855-865.e9
pubmed: 33979649
Proc Soc Exp Biol Med. 1966 Jan;121(1):190-3
pubmed: 4285768
Res Rep Urol. 2020 Dec 15;12:639-649
pubmed: 33365282
Nat Commun. 2023 Mar 28;14(1):1733
pubmed: 36977673
Science. 2020 May 22;368(6493):829-830
pubmed: 32385101
Nature. 2020 Jun;582(7811):289-293
pubmed: 32272481
ChemMedChem. 2022 Jan 5;17(1):e202100455
pubmed: 34423563
Front Pharmacol. 2020 Aug 07;11:1189
pubmed: 32848790
Sci Rep. 2021 Jun 24;11(1):13208
pubmed: 34168183
Front Pharmacol. 2021 Mar 23;12:633680
pubmed: 33833683
Nature. 2021 Aug;596(7873):482-485
pubmed: 34433937
N Engl J Med. 2020 Nov 5;383(19):1813-1826
pubmed: 32445440
Cell. 2020 Apr 16;181(2):223-227
pubmed: 32220310
Virus Res. 2020 Dec;290:198169
pubmed: 32979476
Antiviral Res. 2018 Feb;150:155-163
pubmed: 29289665
Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082
pubmed: 29126136
Gastroenterology. 2020 Sep;159(3):1129-1131.e3
pubmed: 32446698
Nature. 2020 Jul;583(7816):459-468
pubmed: 32353859
Pharmacol Ther. 2021 Dec;228:107930
pubmed: 34174275
Nat Commun. 2021 Jan 20;12(1):488
pubmed: 33473130
J Biol Chem. 2020 May 15;295(20):6785-6797
pubmed: 32284326
Antiviral Res. 2018 Jan;149:58-74
pubmed: 29128390
Lancet. 2003 Apr 19;361(9366):1319-25
pubmed: 12711465
Nature. 2020 Oct;586(7827):113-119
pubmed: 32707573
Br Med J. 1965 Jun 5;1(5448):1467-70
pubmed: 14288084
J Virol. 2005 Dec;79(24):15199-208
pubmed: 16306591
Nature. 2020 Mar;579(7798):265-269
pubmed: 32015508
ACS Pharmacol Transl Sci. 2020 Oct 09;3(6):1265-1277
pubmed: 33330841
Sci Adv. 2020 Oct 16;6(42):
pubmed: 33067239
Front Chem. 2022 Feb 23;10:822785
pubmed: 35281561