TheSARScoronavirusLifeCycle

Severe Acute Respiratory Syndrome (SARS) has affected thousands of individuals, causing fever, and pneumonia with a mortality rate estimated at 10-18%. A novel coronavirus has been identified as the cause agent and its genome has been sequenced. Human coronaviruses cause mild respiratory illness and accounts for about a third of all cases of the common cold. The enveloped SARS virus contains a large + strand RNA genome, approximately 30,000 nucleotides. Examination of the SARS coronavirus sequences reveals that rep gene covers over 20,000 nucleotides and encodes two overlapping polyproteins cleaved by viral proteases into smaller protein products. Translation of the longer polyprotein encoded by the rep gene requires a ribosomal frameshift. Other viral genes are predicted to encode the transmembrane spike protein S involved in viral fusion with host cells, the envelope protein E, the membrane protein M and the nucleocapsid protein N that binds to the RNA genome as well as several additional open reading frames with unknown functions. Viral entry into the cell is followed by translation of the viral rep gene, which codes for a viral protease within the polyprotein, Mpro or 3CLpro. The SARS 3CLpro has also been verified in vitro to cleave after the Gln residue at Leu-Gln-(Ser, Ala, Gly),. Polypeptides released from the polyproteins by the main viral protease Mpro or 3CLpro include the viral polymerase and a protease. Both products are essential for viral replication and transcription. Structural crystals of a porcine coronavirus protease with a transition state inhibitor suggest that inhibitors of the distantly related rhinovirus protease like the drug AG7088 may be modified to produce drugs that block the SARS protease and viral replication. Blocking entry of the SARS virus into cells, involving recognition of cellular receptors by the S spike protein, may provide another strategy for the development of drugs to treat SARS.

Contributor: Kosi Gramatikoff, PhD, Glenn Croston, PhD

REFERENCES: Kanchan A et al. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. Science, Published online 13 May 2003 Marco A. Marra et al. The Genome Sequence of the SARS-Associated Coronavirus Science, Published online 1 May 2003 Paul A. Rota et al. Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome. Science, Published online 1 May 2003