Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target.
Sarah WazirTomi A O ParviainenJessica J PfannenstielMen Thi Hoai DuongDaniel CluffSven T SowaAlbert Galera-PratDana V FerrarisMirko M MaksimainenAnthony R FehrJuha P HeiskanenLari LehtiöPublished in: Journal of medicinal chemistry (2024)
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC 50 of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27 . Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- small molecule
- drug resistant
- immune response
- single cell
- protein protein
- multidrug resistant
- acinetobacter baumannii
- stem cells
- high throughput
- toll like receptor
- dendritic cells
- mass spectrometry
- drug delivery
- bone marrow
- cell therapy
- inflammatory response
- cystic fibrosis
- disease virus
- transcription factor
- dual energy
- structure activity relationship