In vitro interaction of potential antiviral TMPRSS2 inhibitors with human serum albumin and cytochrome P 450 isoenzymes.
Antiviral Agents
/ analysis
Cytochrome P-450 Enzyme System
/ metabolism
Dose-Response Relationship, Drug
Humans
Isoenzymes
/ metabolism
Microsomes, Liver
/ drug effects
Protease Inhibitors
/ analysis
Protein Binding
/ physiology
Serine Endopeptidases
/ analysis
Serum Albumin, Human
/ metabolism
Spectrometry, Fluorescence
/ methods
Tandem Mass Spectrometry
/ methods
3-amidinophenylalanine
Cytochrome P450 enzymes
SARS-CoV-2, human serum albumin
TMPRSS2
Trypsin-like serine proteases
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
22
09
2021
revised:
24
11
2021
accepted:
06
12
2021
pubmed:
17
12
2021
medline:
27
1
2022
entrez:
16
12
2021
Statut:
ppublish
Résumé
The interactions of four sulfonylated Phe(3-Am)-derived inhibitors (MI-432, MI-463, MI-482 and MI-1900) of type II transmembrane serine proteases (TTSP) such as transmembrane protease serine 2 (TMPRSS2) were examined with serum albumin and cytochrome P450 (CYP) isoenzymes. Complex formation with albumin was investigated using fluorescence spectroscopy. Furthermore, microsomal hepatic CYP1A2, 2C9, 2C19 and 3A4 activities in presence of these inhibitors were determined using fluorometric assays. The inhibitory effects of these compounds on human recombinant CYP3A4 enzyme were also examined. In addition, microsomal stability assays (60-min long) were performed using an UPLC-MS/MS method to determine depletion percentage values of each compound. The inhibitors showed no or only weak interactions with albumin, and did not inhibit CYP1A2, 2C9 and 2C19. However, the compounds tested proved to be potent inhibitors of CYP3A4 in both assays performed. Within one hour, 20%, 12%, 14% and 25% of inhibitors MI-432, MI-463, MI-482 and MI-1900, respectively, were degraded. As essential host cell factor for the replication of the pandemic SARS-CoV-2, the TTSP TMPRSS2 emerged as an important target in drug design. Our study provides further preclinical data on the characterization of this type of inhibitors for numerous trypsin-like serine proteases.
Identifiants
pubmed: 34915414
pii: S0753-3322(21)01300-7
doi: 10.1016/j.biopha.2021.112513
pmc: PMC8668183
pii:
doi:
Substances chimiques
Antiviral Agents
0
Isoenzymes
0
Protease Inhibitors
0
Cytochrome P-450 Enzyme System
9035-51-2
Serine Endopeptidases
EC 3.4.21.-
TMPRSS2 protein, human
EC 3.4.21.-
Serum Albumin, Human
ZIF514RVZR
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112513Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Références
J Med Chem. 1997 Sep 12;40(19):3091-9
pubmed: 9301673
Mycotoxin Res. 2018 Nov;34(4):269-278
pubmed: 30014206
Drug Des Devel Ther. 2018 May 08;12:1147-1156
pubmed: 29780235
Future Microbiol. 2020 Dec;15:1747-1758
pubmed: 33404263
Viruses. 2020 Jun 10;12(6):
pubmed: 32532094
Eur J Cell Biol. 2015 Jul-Sep;94(7-9):375-83
pubmed: 26095298
Prog Mol Biol Transl Sci. 2011;99:1-50
pubmed: 21238933
J Enzyme Inhib Med Chem. 2016;31(sup2):123-129
pubmed: 27277342
Science. 2020 Apr 24;368(6489):409-412
pubmed: 32198291
Cell. 2020 Aug 6;182(3):734-743.e5
pubmed: 32643603
Bioorg Med Chem Lett. 1999 Nov 1;9(21):3147-52
pubmed: 10560742
J Enzyme Inhib Med Chem. 2021 Dec;36(1):659-668
pubmed: 33641565
Virology. 2008 Mar 1;372(1):127-35
pubmed: 18022664
Science. 2021 May 7;372(6542):642-646
pubmed: 33811162
Chem Rev. 2004 Sep;104(9):3947-80
pubmed: 15352783
Life Sci Alliance. 2020 Jul 23;3(9):
pubmed: 32703818
Mol Aspects Med. 2012 Jun;33(3):209-90
pubmed: 22230555
J Virol. 2014 May;88(9):4744-51
pubmed: 24522916
Nat Commun. 2021 Feb 8;12(1):866
pubmed: 33558541
J Pharm Biomed Anal. 2018 Feb 20;150:39-42
pubmed: 29216583
Biochem J. 2013 Jun 1;452(2):331-43
pubmed: 23527573
Int J Biochem Cell Biol. 2008;40(6-7):1297-316
pubmed: 18191610
J Biol Chem. 2001 Jan 12;276(2):857-60
pubmed: 11060317
Biomed Pharmacother. 2018 Jun;102:912-921
pubmed: 29710546
J Pharm Biomed Anal. 2015 Mar 25;107:325-32
pubmed: 25637820
Nat Rev Drug Discov. 2004 Aug;3(8):649-59
pubmed: 15286732
J Virol. 2011 May;85(9):4122-34
pubmed: 21325420
Biochim Biophys Acta. 2013 Dec;1830(12):5435-43
pubmed: 23665585
Biomed Pharmacother. 2018 Nov;107:777-784
pubmed: 30142539
Arch Toxicol. 2020 Nov;94(11):3671-3722
pubmed: 33111191
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Antimicrob Agents Chemother. 2020 May 21;64(6):
pubmed: 32312781
Drug Metab Dispos. 2020 Oct;48(10):1064-1073
pubmed: 32661014
ACS Med Chem Lett. 2012 Apr 11;3(7):530-4
pubmed: 24900505