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RESEARCH PRODUCT
Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
Christoph A. SotrifferRamakanth MadhugiriCollin ZimmerJohn ZiebuhrStefan HammerschmidtArmin WelkerPatrick MüllerHannah MausRobert A. ZimmermannChristian KerstenTanja SchirmeisterChristin Müllersubject
Computational chemistryProteases2019-20 coronavirus outbreakCoronavirus disease 2019 (COVID-19)medicine.medical_treatmentSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)virusesStructure-activity relationshipsCysteine Proteinase InhibitorsIsoindolesCrystallography X-RayVirus Replicationmedicine.disease_causeAntiviral Agents01 natural sciencesBiochemistryDrug designStructure-Activity Relationshipchemistry.chemical_compoundCatalytic DomainChlorocebus aethiopsDrug DiscoverymedicineAnimalsddc:610General Pharmacology Toxicology and PharmaceuticsBenzamideVero CellsCoronavirus 3C ProteasesCoronavirusPharmacologyProteaseMolecular StructureFull PaperSARS-CoV-2010405 organic chemistryOrganic ChemistryFull PapersProtease inhibitors0104 chemical sciencesMolecular Docking Simulation010404 medicinal & biomolecular chemistrychemistryBiochemistryBenzamidesddc:540Molecular MedicineProtein BindingCysteinedescription
Abstract Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PLpro are valuable starting points for the development of new pan‐coronaviral inhibitors.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-10-16 |