STORM Therapeutics has announced the development of novel inhibitors targeting the coronavirus methyltransferase NSP14. These inhibitors exhibit potent antiviral activity across a range of viruses, including those with pandemic potential, by preventing viral replication and enhancing the host immune response. The findings were presented at ELRIG Drug Discovery 2024.
The RNA genome of SARS-CoV-2 contains a 5' cap crucial for viral protein translation, protection from exonucleases, and evasion of the host immune response. Coronaviruses produce their own capping enzymes, including RNA methyltransferases, making them attractive drug targets.
Identification and Optimization of Viral-Specific Inhibitors
STORM Therapeutics has identified and optimized viral-specific inhibitors using a small molecule inhibitor profiling assay cascade. Key compounds like STM10927 demonstrate single-digit picomolar binding and a very slow off-rate in single-cycle kinetic surface plasmon resonance (SCK-SPR) assays. The SPR binding data correlates strongly with antiviral cell potency against SARS-CoV-2 in A549-ACE2-TMPRSS2 (AAT) cells. Furthermore, STORM's methyltransferase inhibitors exhibit virus specificity, as shown by profiling STM10155 in a human methyltransferase panel.
Broad-Spectrum Antiviral Activity and Drug-Like Properties
These compounds demonstrate good drug-like properties and potent cellular activity across the coronavirus family. STORM compounds show significantly improved potency against SARS-CoV-2 in A549-ACE2-TMPRSS2 cells compared to Nirmatrelvir, the active component of Paxlovid. The compounds exhibit antiviral cellular potency for various coronavirus subgenera, including SARS-CoV-2, MERS, HuCoV-229E, HuCoV-OC43, PgCov/GD/2019, MHV, and the emergent bat strain SHC14, with no cytotoxicity observed below 10 uM in multiple cell lines. STM10189 effectively inhibits SARS-CoV-2 infection in human airway epithelial cells grown at an air-liquid interface (HAE-ALI). STM10640 has a predicted oral dose of 8.5 mg/kg BID in humans to cover 4x unbound IC90 at Cmin. Recent potent analogs have improved cell potency, human hepatocyte stability, and fraction absorbed in rodent in-vivo PK, with physicochemical properties within drug-like space.
Novel Platform for Antiviral Drug Discovery
Structural analysis reveals that SAM/SAH, the methyltransferase cofactor/by-product, binds to viral methyltransferases in a similar conformation, suggesting potential for pan-viral activity. Preliminary data indicates that STM compounds specifically inhibit viral replication of flaviviruses Yellow Fever and Dengue-3 in cell-based reporter assays, with no cytotoxicity up to 30 uM.
These findings highlight the potential of STORM Therapeutics' NSP14 inhibitors as a novel platform for antiviral drug discovery, offering a dual mechanism of action by inhibiting viral replication and activating the host's innate immune response.
