Structural Analysis for Antiviral Compounds

Structural Analysis for Antiviral Compounds

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • The coronavirus main protease (M(pro)) is critical in viral gene expression (Xue et al., 2008).
  • The viral replication through the proteolytic processing of replicase polyproteins may be a potential antiviral target.
  • The crystal structures of infectious bronchitis virus (IBV) M(pro) and SARS-CoV M(pro) mutant (H41A) are important.
  • The structures of the N-terminal autocleavage substrate are also critical.
  • These structures can be used to describe the structural flexibility and substrate binding of M(pro).
  • A monomeric form of IBV M(pro) was identified in CoV M(pro) structures.
  • A comparison of these M(pro) structures may be helpful for the design of substrate-based inhibitors targeting CoV M(pro)s.
  • A Michael acceptor inhibitor (N3) was co-crystallized with IBV M(pro) and led to inactivation of IBV M(pro).
  • The structure-based optimization of N3 has led to compounds N27 and H16 that may inhibit SARS-CoV M(pro) (Xue et al., 2008).

A Potential Antiviral Molecule for SARS-CoV and Ebola

(From Potential Antiviral Agents for Coronaviruses: Compounds, Herbal Products, and Drug Targets)

  • SARS-CoV and Ebola, Hendra, and Nipah viruses belong to different viral families.
  • These viruses need cathepsin L for entering their target cells (Elshabrawy et al., 2014).
  • The viral glycoproteins are primed by protease cleavage before fusing with the host cell membrane (Elshabrawy et al., 2014).
  • A high-throughput assay has been used to identify small molecules that can prevent cathepsin L cleavage of viral glycoproteins.
  • A broad-spectrum small molecule was able to inhibit the cathepsin L-mediated cleavage and the entry of glycoprotein pseudotypes.
  • The small molecule may be a candidate as a broad-spectrum antiviral drug against these viruses (Elshabrawy et al., 2014).

References:

Elshabrawy, H. A., Fan, J., Haddad, C. S., Ratia, K., Broder, C. C., Caffrey, M., & Prabhakar, B. S. (2014). Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay. Journal of Virology, 88(8), 4353–4365. https://doi.org/10.1128/JVI.03050-13

Xue, X., Yu, H., Yang, H., Xue, F., Wu, Z., Shen, W., Li, J., Zhou, Z., Ding, Y., Zhao, Q., Zhang, X. C., Liao, M., Bartlam, M., & Rao, Z. (2008). Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design. Journal of Virology, 82(5), 2515–2527. https://doi.org/10.1128/JVI.02114-07

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