Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development.
Hannes BergMaria Alexandra Wirtz MartinNadide AltincekicIslam AlshamlehJasleen Kaur BainsJulius BlecharBetül CeylanVanessa de JesusKarthikeyan DhamotharanChristin FuksSantosh L GandeBruno HargittayKatharina F HohmannMarie T HutchisonSophie Marianne KornRobin KrishnathasFelicitas KutzVerena LinhardTobias MatzelNathalie MeiserAnna NiesterukDennis J PyperLinda SchulteSven TrucksKamal AzzaouiMarcel J J BlommersYojana GadiyaReagon KarkiAndrea ZalianiPhilip GribbonMarcius da Silva AlmeidaCristiane Dinis AnobomAnna L BulaMatthias BütikoferÍcaro Putinhon CarusoIsabella C FelliAndrea T Da PoianGisele Cardoso de AmorimNikolaos K FourkiotisAngelo GalloDhiman GhoshFrancisco Gomes-NetoOksana GorbatyukBing HaoVilius KurauskasLauriane LecoqYunfeng LiNathane Cunha Mebus-AntunesMiguel MompeánThais Cristtina Neves-MartinsMartí Ninot-PedrosaAnderson S PinheiroLetizia PontorieroYulia PustovalovaRoland RiekAngus J RobertsonMarie Jose Abi SaadMiguel Á TreviñoAikaterini C TsikaFabio Ceneviva Lacerda AlmeidaAdriaan BaxKatherine A Henzler-WildmanJeffrey C HochKristaps JaudzemsDouglas V LaurentsJulien OrtsRoberta PierattelliGeorgios A SpyrouliasElke Duchardt-FernerJan FernerBoris FürtigMartin HengesbachFrank LoehrNusrat S QureshiChristian RichterKrishna SaxenaAndreas SchlundtSridhar SreeramuluAnna WackerJulia E WeigandJulia Wirmer-BartoschekJens WöhnertHarald SchwalbePublished in: Angewandte Chemie (International ed. in English) (2022)
SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.