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Chapter 12 : Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
Authors:
Dale L. Barnard1,
Yohichi Kumaki2
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Affiliations:
1: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322-5600;
2: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, Utah State University, Logan, UT 84322-5600
Content Type: Monograph
Publication Year:
2009
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
Book DOI:
10.1128/9781555815493
Chapter DOI:
10.1128/9781555815493.ch12
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Abstract:
Severe acute respiratory syndrome (SARS) is the first new infectious disease of this century, caused by a novel human coronavirus (SARS-CoV), and the disease is associated with severe pulmonary pathological features leading to high mortality. This chapter talks about different kinds of inhibitors such as small-molecule inhibitors, peptide, and papain-like proteinase inhibitors. SARS-CoV is a positive-sense single-stranded (ss) RNA virus. The 30-kb genome is predicted to encode at least 10 open reading frames (ORF), some of which encode proteins involved in virus entry into cells. Receptor-virus interaction can be inhibited using two approaches. First, develop inhibitors that block the cellular receptor with which the virus attachment protein interacts. Second, block the domain in the virus attachment protein that binds to the cellular receptor. Researchers have determined the crystal structures of human coronavirus 3CLpro and suggested that the rhinovirus 3CLpro inhibitor AG7088 could serve as a starting point for an anti-SARS drug based on the theoretical homology model of SARS-CoV 3CLpro. Researchers have showed that the RNAi targeting of the coronavirus RdRp using synthesized short hairpin expression plasmids significantly reduced the expression of target protein in 293 cells and HeLa cells and blocked plaque formation of SARS-CoV in Vero E6 cells. Development of inhibitors of the innate immune response might also be worthwhile, with the caveat that humans, like animals, are reservoirs of mixed infections, latent, chronic, and acute, and that down-regulating an immune response to ameliorate a SARS infection may exacerbate a coexisting infection from another infectious agent.
Citation:
Barnard D, Kumaki Y.
2009.
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus,
p 209-222.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch12
Figures
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
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Citation:
Barnard D, Kumaki Y.
2009.
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus,
p 209-222.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch12
/content/10.1128/9781555815493.ch12.ch12fig01
Figure 1.
Spike protein of SARS-CoV and gp41 of HIV-1 are illustrated in parallel. When they contact each other, CP-1 and NP-1 of S protein of SARS-CoV and corresponding HIV-1 protein DP-107 and DP-178 form coil structures. After the process, the conformational changes of S1 or gp41 occur and induce fusion between infected and uninfected cells.
10.1128/9781555815493/f0212-01_thmb.gif
10.1128/9781555815493/f0212-01.gif
Figure 1.
Spike protein of SARS-CoV and gp41 of HIV-1 are illustrated in parallel. When they contact each other, CP-1 and NP-1 of S protein of SARS-CoV and corresponding HIV-1 protein DP-107 and DP-178 form coil structures. After the process, the conformational changes of S1 or gp41 occur and induce fusion between infected and uninfected cells.
Citation:
Barnard D, Kumaki Y.
2009.
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus,
p 209-222.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch12
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Tables
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
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Citation:
Barnard D, Kumaki Y.
2009.
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus,
p 209-222.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch12
/content/10.1128/9781555815493.ch12.ch12tab01
Table 1.
Potential targets of inhibition of SARS-CoV by antiviral agents
a
Table 1.
Potential targets of inhibition of SARS-CoV by antiviral agents a
Citation:
Barnard D, Kumaki Y.
2009.
Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus,
p 209-222.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch12