Publication date: Sep 05, 2025
We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.
| Concepts | Keywords |
|---|---|
| Nanomolar | Activity |
| Nsp14 | Antiviral |
| Pharmacological | Cellular |
| Target | Complex |
| Viral | Cov |
| Crystal | |
| Inhibition | |
| Inhibitor | |
| Inhibitors | |
| Non | |
| Nsp14 | |
| Nucleoside | |
| Sars | |
| Validated | |
| Viral |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | Guanine |
| disease | IDO | protein |
| disease | IDO | role |
| disease | IDO | assay |
| disease | MESH | COVID-19 |