PMID- 35099120
OWN - NLM
STAT- MEDLINE
DCOM- 20220315
LR  - 20221207
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 17
IP  - 5
DP  - 2022 Mar 4
TI  - Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent 
      Anti-SARS-CoV-2 Activity.
PG  - e202100732
LID - 10.1002/cmdc.202100732 [doi]
LID - e202100732
AB  - Naturally occurring compounds represent a vast pool of pharmacologically active 
      entities. One of such compounds is andrographolide, which is endowed with many 
      beneficial properties, including the activity against severe acute respiratory 
      syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit 
      optimization campaign, it is imperative to unravel the primary mechanism(s) of 
      the antiviral action of andrographolide. Here, we showed by means of a reporter 
      gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting 
      the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear 
      factor erythroid 2-related factor 2 (NRF2) causing NRF2 upregulation. Moreover, 
      we demonstrated that subtle structural modifications of andrographolide could 
      lead to derivatives with stronger on-target activities and improved 
      physicochemical properties. Our results indicate that further optimization of 
      this structural class is warranted to develop novel COVID-19 therapies.
CI  - (c) 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
FAU - Schulte, Bianca
AU  - Schulte B
AD  - Institute of Virology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, 
      Germany.
FAU - Konig, Maria
AU  - Konig M
AD  - Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, 04318, 
      Leipzig, Germany.
FAU - Escher, Beate I
AU  - Escher BI
AUID- ORCID: 0000-0002-5304-706X
AD  - Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, 04318, 
      Leipzig, Germany.
AD  - Center for Applied Geoscience, Eberhard Karls University Tubingen, 72076, 
      Tubingen, Germany.
FAU - Wittenburg, Sophie
AU  - Wittenburg S
AUID- ORCID: 0000-0003-0242-5726
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
FAU - Proj, Matic
AU  - Proj M
AUID- ORCID: 0000-0003-4043-9686
AD  - Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, 1000, Ljubljana, 
      Slovenia.
FAU - Wolf, Valentina
AU  - Wolf V
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
FAU - Lemke, Carina
AU  - Lemke C
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
FAU - Schnakenburg, Gregor
AU  - Schnakenburg G
AUID- ORCID: 0000-0001-6489-2106
AD  - Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 
      53121, Bonn, Germany.
FAU - Sosic, Izidor
AU  - Sosic I
AUID- ORCID: 0000-0002-3370-4587
AD  - Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, 1000, Ljubljana, 
      Slovenia.
FAU - Streeck, Hendrik
AU  - Streeck H
AUID- ORCID: 0000-0002-0335-6390
AD  - Institute of Virology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, 
      Germany.
AD  - German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Germany.
FAU - Muller, Christa E
AU  - Muller CE
AUID- ORCID: 0000-0002-0013-6624
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
FAU - Gutschow, Michael
AU  - Gutschow M
AUID- ORCID: 0000-0002-9376-7897
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
FAU - Steinebach, Christian
AU  - Steinebach C
AUID- ORCID: 0000-0001-5638-1955
AD  - Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, 
      Germany.
LA  - eng
GR  - 9 A894/Volkswagen Foundation/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220131
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Antiviral Agents)
RN  - 0 (Diterpenes)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 410105JHGR (andrographolide)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/*chemistry/*pharmacology
MH  - COVID-19/virology
MH  - Cell Line
MH  - Chlorocebus aethiops
MH  - Diterpenes/*chemistry
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/metabolism
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - NF-E2-Related Factor 2/metabolism
MH  - SARS-CoV-2/*drug effects/physiology
MH  - Vero Cells
MH  - Virus Replication
MH  - COVID-19 Drug Treatment
PMC - PMC9015489
OTO - NOTNLM
OT  - KEAP1/NRF2
OT  - SARS-CoV-2
OT  - andrographolide
OT  - medicinal chemistry
OT  - natural products
COIS- The authors declare no conflict of interest.
EDAT- 2022/02/01 06:00
MHDA- 2022/03/16 06:00
PMCR- 2022/01/31
CRDT- 2022/01/31 08:44
PHST- 2022/01/13 00:00 [revised]
PHST- 2021/11/24 00:00 [received]
PHST- 2022/02/01 06:00 [pubmed]
PHST- 2022/03/16 06:00 [medline]
PHST- 2022/01/31 08:44 [entrez]
PHST- 2022/01/31 00:00 [pmc-release]
AID - CMDC202100732 [pii]
AID - 10.1002/cmdc.202100732 [doi]
PST - ppublish
SO  - ChemMedChem. 2022 Mar 4;17(5):e202100732. doi: 10.1002/cmdc.202100732. Epub 2022 
      Jan 31.