Characterization and Inhibition of SARS-Coronavirus Main Protease

Abstract

Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel human coronavirus (CoV). During the 2003 epidemic, the disease rapidly spread from its origin in southern China to other countries and affected almost 8000 patients, which resulted in about 800 fatalities. A chymotrypsin-like cysteine protease named 3C-like protease (3CLpro) is essential for the life cycle of the SARS-CoV. This main protease is responsible for maturation of functional proteins and represents a key anti-viral target. HPLC and fluorescence-based assays have been used to characterize the protease and to determine the potency of the inhibitors. The fluorogenic method monitoring the increase of fluorescence from the cleavage of a peptide substrate containing an Edans-Dabcyl fluorescence quenching pair at two ends has enabled the use of high throughput screening to speed up the drug discovery process. Several groups of inhibitors have been identified through high throughput screening and rational drug design approaches. Thus, alpha,beta-unsaturated peptidomimetics, anilides, metal-conjugated compounds, boronic acids, quinolinecarboxylate derivatives, thiophenecarboxylates, phthalhydrazide-substituted ketoglutamine analogues, isatin and natural products have been identified as potent inhibitors of the SARS-CoV main protease. The different classes of inhibitors reported in these studies are summarized in this review. Some of these inhibitors could be developed into potential drug candidates, which may provide a solution to combat possible reoccurrence of the SARS and other life-threatening viruses with 3CL proteases.

Evaluation of Immunomodulators, Interferons and Known in Vitro SARS-CoV Inhibitors for Inhibition of SARS-Cov Replication in BALB/c Mice

“…It has the potential to inhibit the two proteases of SARS-CoV that are responsible for virus maturation (Lindner et al, 2005;Liang, 2006) (Barnard et al, 2006). Therefore, the compound was evaluated for efficacy against SARS-CoV replication in the mouse as an i.p.…”

The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease

“…The catalytic dyad Cys148-His41 and the substrate binding site of pro are located on the interface of Domain I and II, which is identified by the bound inhibitor N3 (Fig. 1B) (Liang, 2006;Lee et al, 2009). Although the inhibitory effect of inhibitor N3 to HCoV-EMC 3CL pro is not extremely good, it presents good pharmaceutical properties with comparable inhibitory activity (Fig.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Protease inhibitors have also been reviewed elsewhere (Liang, 2006;Ramajayam et al, 2011). In addition to its role in proteolytic processing of the viral polymerase, PLP2 is also involved in host evasion.…”