The COVID-19 pandemic caused by the SARS-CoV-2 remains a global public health crisis. An effective way to fight against COVID-19 is a vaccine plus a drug (via oral administration). Identification of proteins that is critical for virus replication will provide guidance for searching drugs quickly1. SARS-CoV-2 genome encodes 16 non-structural proteins with multiple enzymatic functions2. Among them, metalloenzymes are crucial for the virulence and replication of virus and are the potential targets. Nsp13 (i.e. helicase) is considering as a promising drug target due to its unique structure and function3. It consists of zinc-finger domain, stalk domain, 1B domain, 1A domain and 2A domain, possessing the RNA helicase and ATPase activities. 

Historically, metal compounds have been used as antimicrobial agents, but their antiviral activities have rarely been explored. Previously, we found that bismuth citrate-containing drugs and other bismuth-based complexes exhibited inhibition towards both the ATPase and DNA-unwinding activities of the SARS-CoV-2 helicase via an irreversible displacement of Zn(II) from the enzyme by Bi(III), highlighting nsp13, a perfect target for anti-coronavirus drugs and the clinical potential of Bi(III) drugs or other metallodrugs for the treatment of COVID-194. Here, we report discovery of potent inhibitors targeting helicase among a battery of metallodrugs (i.e. Bi(III)- and Au(I)-containing drugs). We subsequently examined their mode of inhibition, validated in vivo activity in hamsters. We aim to develop a more effective antiviral drug to combat COVID-19 disease based on the nsp13.

This work was supported by the Research Grants Council (RGC, 17318322, 2122-7S04), ITF (ITS/278/20) of Hong Kong SAR and the University of Hong Kong.

References

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(2) Robson, F.; Khan, K. S.; Le, T. K.; Paris, C.; Demirbag, S.; Barfuss, P.; Rocchi, P.; Ng, W. L. Mol Cell 2020, 79 (5), 710-727. 

(3) Li, H.; Yuan, S.; Wei, X.; Sun, H. Chem Comm 2022, 58, 7466-7482..

(4) (a) Yuan, S.; Wang, R.; Chan, J. F.; Zhang, A. J.; Cheng, T.; Chik, K. K.; Ye, Z. W.; Wang, S.; Lee, A. C.; Jin, L.; Yuen, K.Y., Sun, H. et al. Nat Microbiol 2020, 5, 1439-1448. (b) Wang, R.M., Chan, J.F.W., Wang, S.Y.,… Li, H., Yuen, K.Y., Yuan, S.F., Sun, H. Chem Sci 2022, 13, 2238-2248.