Chris McCurrin

Introduction: SARS-CoV 2 is the Betacoronavirus that causes COVID-19¹. First identified in Wuhan, China in 2019, it was declared a “global pandemic” by the WHO in March 2020^2-3. It has been responsible for 6.25 million deaths since that time⁴. Treatment of COVID-19 remains primarily supportive^2-3. While pharmacological agents exist, they all have limited applications, and some of the antibody therapies are no longer effective against emerging variants^2,3,5. As such, drug development continues to be an important area of study. One of SARS-CoV 2’s proteins, nonstructural protein 16 (NSP16), is an attractive target for drug development. Acting as a 2’ O-methyltransferase, it performs the last step in synthesizing a 5’ cap on the viral RNA, preventing recognition by the host innate immune system¹, and a recent study shows that it also decreases interferon signaling by inhibiting splicing of host mRNA⁶. Methods: PubMed was searched for articles either suggestive of NSP16’s potential as a drug target or detailing attempts to develop inhibitors of the protein. The crystal structure of NSP16 was solved by x-ray crystallography and compared to those of other Betacoronaviruses⁷. The active site of NSP16 was mutated in MERS-CoV, and viral replication and disease severity were tested in cell culture and mice⁸. The crystal structure was used to design compounds that would selectively inhibit NSP16, which were tested for inhibition and cell permeability⁹. Lastly, DZNep, a known methyltransferase inhibitor, was evaluated via Western blot and CHIP assay for effects on viral protein translation¹⁰.  Results: NSP16’s structure remains highly conserved when compared to those of SARS-CoV and MERS-CoV, suggesting that similar effects would be seen with inhibition of NSP16 in all species⁷. Mutation of the active site of NSP16 in MERS-CoV resulted in significantly decreased viral replication and decreased disease severity in mice⁸. Of the compounds designed to inhibit NSP16, none were selective for it over human methyltransferases, and none penetrated cell membranes⁹. DZNep significantly decreased viral protein translation and interaction with eukaryotic translation initiation factor 4E¹⁰. Conclusion: NSP16 is crucial for successful infection by SARS-CoV 2; therefore, its inhibition is an attractive strategy for treatment of COVID-19. Unfortunately, no useful drugs have yet been identified. Although DZNep shows promise, its effects on human methyltransferases make it unlikely to progress to clinical trials. However, this avenue of drug development seems to be worth pursuing, and the structure guided approach described above appears to be a good place to invest further research.

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