Influenza viruses are negative-sense, single-stranded RNA viruses that infect the upper, and occasionally the lower, respiratory tracts In the US. Illness from infections by influenza virus has caused an average of approximately 36,000 deaths from 1990-1999 and 226,000 hospitalizations during 1979-2001 (Thompson, W. W., et al. PMID: 15367555), (Thompson, W. W., et al. PMID:12517228). Influenza A more ..
Table of Contents
Target
Depositor Specified Assays
| AID | Name | Type | Comment |
|---|---|---|---|
| 504329 | Discovery of Small Molecule Probes for H1N1 Influenza NS1A | confirmatory | Primary and Confirmatory screen. |
| 540254 | Discovery of Small Molecule Probes for H1N1 NS1a - H1N1 (KY180) Influenza Antiviral Screen | confirmatory | Secondary Influenza Antiviral Screen of H1N1 (KY180) |
| 540296 | Discovery of Small Molecule Probes for H1N1 NS1a - H1N1 Influenza MDCK Cytotoxicity Screen | confirmatory | |
| 540298 | Discovery of Small Molecule Probes for H1N1 NS1a - H1N1 Influenza Vero E6 Cytotoxicity Screen | confirmatory | |
| 540257 | Discovery of Small Molecule Probes for H1N1 NS1a - H1N1 (KY136) Influenza Antiviral Screen | confirmatory |
Description:
Influenza viruses are negative-sense, single-stranded RNA viruses that infect the upper, and occasionally the lower, respiratory tracts In the US. Illness from infections by influenza virus has caused an average of approximately 36,000 deaths from 1990-1999 and 226,000 hospitalizations during 1979-2001 (Thompson, W. W., et al. PMID: 15367555), (Thompson, W. W., et al. PMID:12517228). Influenza A viruses (IAV), which also infect a wide number of avian and mammalian species, pose a considerable public health burden with epidemic and pandemic potential. This is particularly evident with the new strain of "swine flu virus" which emerged recently in Mexico and spread to different parts of the North America (MMWR Morb Mortal Wkly Rep PMID:19390508). The most devastating IAV pandemic occurred in 1918 which resulted in approximately 30 million deaths worldwide (Reid, A. H., et al. PMID: 11226857).
Antivirals are widely used in treatment of epidemic and pandemic IAV infections. Certainly, the lack of availability of vaccines early in IAV pandemics has driven the search for effective antivirals. One potential and largely unexplored IAV target is to disarm viral proteins that modulate the host's antiviral response. NS1A protein is a critical viral protein in this regard. During viral infection, infected cells of the host mount a potent and diverse antiviral defense response to prevent virus proliferation (Randall, R. E., et al. PMID: 18089727). To perpetuate, IAV have evolved multiple mechanisms to circumvent these host defense mechanisms. Strategies include those which are strain-specific such as increased replication speed (Grimm, D., et al. PMID: 17426143), (Kurokawa, M., et al. PMID: 10202186) or those that reduce sensitivity to host-cell antiviral defense mechanisms (Dittmann, J., et al. PMID: 17970694). The NS1A protein inhibits the interferon-alpha-beta-induced 2'-5'-oligo synthetase. Drugs that target the NS1A double-stranded (ds) RNA binding domain would inhibit IAV replication.
The N terminus of the NS1A protein (NS1A) of IAV is a highly conserved, multifunctional viral protein which interacts with host dsRNA (Cheng, A., et al. PMID: 18813227). We have developed an AlphaScreen (Perkin Elmer)-based 1536-well high throughput screen (HTS) for NS1A to identify small molecule inhibitors of the dsRNA binding activity. Identification of probes for this activity would provide valuable tools for probing its dsRNA binding function within the cell. Further, this domain could also serve as a target for antiviral drug discovery.
Summary of Primary and Confirmatory Screens for Inhibitors of H1N1 Influenza NS1A
AID 504329
Primary screen test concentration: 12.5 uM
Primary screen activity criterion: Inhibition >=28.99
Number compounds evaluated: 335,445
Number of active compounds: 1,902
Confirmatory concentration range: 100 uM - 0.195 uM
AID 504329
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 1,013
Secondary Antifiviral Screen: H1N1(KY180) Influenza Antiviral Screen
AID 540254
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 7
Secondary Antifiviral Screen: H1N1(KY136) Influenza Antiviral Screen
AID 504257
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 14
Secondary Screen for MDCK Cytotoxicity
AID 504296
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Cell viability <=70% at any tested concentration
Number compounds evaluated (Confirmatory): 15
Number of active compounds (Confirmatory): 13
Secondary Screen for Vero cell Cytotoxicity
AID 504298
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Cell viability <=70% at any tested concentration
Number compounds evaluated (Confirmatory): 15
Number of active compounds (Confirmatory): 10
Antivirals are widely used in treatment of epidemic and pandemic IAV infections. Certainly, the lack of availability of vaccines early in IAV pandemics has driven the search for effective antivirals. One potential and largely unexplored IAV target is to disarm viral proteins that modulate the host's antiviral response. NS1A protein is a critical viral protein in this regard. During viral infection, infected cells of the host mount a potent and diverse antiviral defense response to prevent virus proliferation (Randall, R. E., et al. PMID: 18089727). To perpetuate, IAV have evolved multiple mechanisms to circumvent these host defense mechanisms. Strategies include those which are strain-specific such as increased replication speed (Grimm, D., et al. PMID: 17426143), (Kurokawa, M., et al. PMID: 10202186) or those that reduce sensitivity to host-cell antiviral defense mechanisms (Dittmann, J., et al. PMID: 17970694). The NS1A protein inhibits the interferon-alpha-beta-induced 2'-5'-oligo synthetase. Drugs that target the NS1A double-stranded (ds) RNA binding domain would inhibit IAV replication.
The N terminus of the NS1A protein (NS1A) of IAV is a highly conserved, multifunctional viral protein which interacts with host dsRNA (Cheng, A., et al. PMID: 18813227). We have developed an AlphaScreen (Perkin Elmer)-based 1536-well high throughput screen (HTS) for NS1A to identify small molecule inhibitors of the dsRNA binding activity. Identification of probes for this activity would provide valuable tools for probing its dsRNA binding function within the cell. Further, this domain could also serve as a target for antiviral drug discovery.
Summary of Primary and Confirmatory Screens for Inhibitors of H1N1 Influenza NS1A
AID 504329
Primary screen test concentration: 12.5 uM
Primary screen activity criterion: Inhibition >=28.99
Number compounds evaluated: 335,445
Number of active compounds: 1,902
Confirmatory concentration range: 100 uM - 0.195 uM
AID 504329
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 1,013
Secondary Antifiviral Screen: H1N1(KY180) Influenza Antiviral Screen
AID 540254
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 7
Secondary Antifiviral Screen: H1N1(KY136) Influenza Antiviral Screen
AID 504257
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Inhibition >=30% at any tested concentration
Number compounds evaluated (Confirmatory): 1,815
Number of active compounds (Confirmatory): 14
Secondary Screen for MDCK Cytotoxicity
AID 504296
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Cell viability <=70% at any tested concentration
Number compounds evaluated (Confirmatory): 15
Number of active compounds (Confirmatory): 13
Secondary Screen for Vero cell Cytotoxicity
AID 504298
Confirmatory concentration range: 40 uM - 0.078 uM
Confirmatory activity criterion: Cell viability <=70% at any tested concentration
Number compounds evaluated (Confirmatory): 15
Number of active compounds (Confirmatory): 10
Additional Information
Grant Number: 1 R03 MH089536-01
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