Maria Rosaria Paravati
| From Viral Proteins to Host Targets: Unveiling Casein Kinase 2 as the Antiviral Mechanism of the [4,7]-Phenanthroline Scaffold |
| Paravati Maria Rosaria1, Romeo Isabella 1, Carta Antonio 2, Deiana Andrea 2, Murineddu Gabriele 2 and Alcaro Stefano 1 1 Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Campus “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy 2 Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23a, Sassari, Italy |
| Abstract The [4,7]-phenanthroline compound PS1100 exhibits broad-spectrum activity against several viruses, including SARS-CoV-2 and Zika, making it a compelling scaffold for pan-viral drug discovery [1]. Initially, a computational target fishing study was performed on the key non-structural proteins (NSPs) of SARS-CoV-2 (NSP3, 5, 12, 13, 14, 15, and 16) [2]. However, molecular docking and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) analyses indicated poor affinity for these viral enzymes, a finding corroborated by in vivo assays showing no direct antiviral enzymatic inhibition [3]. This negative outcome prompted a shift toward host-directed therapy, hypothesizing that PS1100 targets cellular factors exploited by viruses, such as Casein Kinase 2 (CK2) [4]. CK2 is a ubiquitous Ser/Thr kinase essential for the replication of numerous viruses. It exists as a heterotetramer with two catalytic (α or α’) and two regulatory (β) subunits, featuring a conserved ATP-binding site and a specific αD pocket [5]. Given its structural similarity to silmitasertib, we investigated PS1100 as a CK2 inhibitor. Our in silico studies showed binding affinities comparable or superior to silmitasertib for the α and α’ subunits, respectively [3]. Thermal Shift Assay (TSA) demonstrated a modest binding affinity, while X-ray crystallography definitively confirmed that PS1100 occupies the CK2 binding pocket. Subsequently, building on these results, a library of 1,945 phenanthroline derivatives was designed, identifying four lead candidates currently under in vitro evaluation. These were used to develop a second library of 266 bivalent molecules, designed to simultaneously target the ATP site and the αD pocket via 5-8 carbon alkyl linkers, inspired by the inhibitor KN2. Ongoing in silico studies are evaluating their binding modes, supporting PS1100 derivatives as promising agents for host-directed, broad-spectrum antiviral strategies. |
| References [1] Carta, A.; Loriga, M.; Paglietti, G.; Ferrone, M.; Fermeglia, M.; Pricl, S.; Sanna, T.; Ibba, C.; La Colla, P.; Loddo, R. Design, synthesis, and preliminary in vitro and in silico antiviral activity of [4,7]phenantrolines and 1-oxo-1,4-dihydro-[4,7]phenantrolines against single-stranded positive-sense RNA genome viruses. Bioorg Med Chem. 2007, 15:1914-27. [2] Kim, D.; Lee, J.Y.; Yang, J.S.; Kim, J.W.; Kim, V.N.; Chang, H. The Architecture of SARS-CoV-2 Transcriptome. Cell. 2020, 181:914-921 [3] Schrödinger, LLC, New York, NY, 2018. [4] Quezada Meza, C.P.; Ruzzene, M. Protein Kinase CK2 and SARS-CoV-2: An Expected Interplay Story. Kinases and Phosphatases. 2023, 1:141-150. [5] Zonta, F.; Borgo, C.; Quezada Meza, C.P.; Masgras, I.; Rasola, A.; Salvi, M.; Pinna, L.A.; Ruzzene M. Contribution of the CK2 Catalytic Isoforms α and α’ to the Glycolytic Phenotype of Tumor Cells. Cells. 2021, 10:181. |