tetano
Editor, Senior Moderator
J Virol. 2013 Nov 6. [Epub ahead of print]
New Small Molecule Entry Inhibitors Targeting Hemagglutinin-mediated Influenza A Virus Fusion.
Basu A, Antanasijevic A, Wang M, Li B, Mills DM, Ames JA, Nash PJ, Williams JD, Peet NP, Moir DT, Prichard MN, Keith KA, Barnard DL, Caffrey M, Rong L, Bowlin TL.
Source
Microbiotix Inc., Worcester, MA 01605, USA.
Abstract
Influenza viruses are a major public health threat worldwide and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. The influenza glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion making it a potential target for the development of anti-influenza drugs. Using pseudotype virus based high throughput screens, we have identified several new small molecules capable of inhibiting influenza virus entry. We prioritized two novel inhibitors, MBX2329 and MBX2546, with aminoalkyl phenol ether and sulfonamide scaffolds respectively, that specifically inhibit HA-mediated viral entry. The two compounds (a) are potent (IC50 = 0.3-5.9 μM), (b) are selective (CC50 >100 μM) with selectivity index (SI) values >20-200 for different influenza strains, (c) inhibit a wide spectrum of influenza A virus that includes the 2009 pandemic influenza A/H1N1/2009, highly pathogenic avian influenza (HPAI) A/H5N1, and oseltamivir resistant A/H1N1 strains, (d) exhibit large volumes of synergy with oseltamivir (36-331 μM2 with 95% confidence) and (e) have chemically tractable structures. Mechanism of action studies suggest that both MBX2329 and MBX2546 bind to HA in a non-overlapping manner. Additional results from HA-mediated hemolysis of chicken red blood cells (cRBCs), competition assay with MAb C179 and mutational analysis suggest that the compounds bind in the stem region of the HA trimer and inhibit HA mediated fusion. Therefore, MBX2329 and MBX2546 represent new starting points for chemical optimization and have the potential to provide valuable future therapeutic options and research tools to study the HA mediated entry process.
PMID:
24198411
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24198411
New Small Molecule Entry Inhibitors Targeting Hemagglutinin-mediated Influenza A Virus Fusion.
Basu A, Antanasijevic A, Wang M, Li B, Mills DM, Ames JA, Nash PJ, Williams JD, Peet NP, Moir DT, Prichard MN, Keith KA, Barnard DL, Caffrey M, Rong L, Bowlin TL.
Source
Microbiotix Inc., Worcester, MA 01605, USA.
Abstract
Influenza viruses are a major public health threat worldwide and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. The influenza glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion making it a potential target for the development of anti-influenza drugs. Using pseudotype virus based high throughput screens, we have identified several new small molecules capable of inhibiting influenza virus entry. We prioritized two novel inhibitors, MBX2329 and MBX2546, with aminoalkyl phenol ether and sulfonamide scaffolds respectively, that specifically inhibit HA-mediated viral entry. The two compounds (a) are potent (IC50 = 0.3-5.9 μM), (b) are selective (CC50 >100 μM) with selectivity index (SI) values >20-200 for different influenza strains, (c) inhibit a wide spectrum of influenza A virus that includes the 2009 pandemic influenza A/H1N1/2009, highly pathogenic avian influenza (HPAI) A/H5N1, and oseltamivir resistant A/H1N1 strains, (d) exhibit large volumes of synergy with oseltamivir (36-331 μM2 with 95% confidence) and (e) have chemically tractable structures. Mechanism of action studies suggest that both MBX2329 and MBX2546 bind to HA in a non-overlapping manner. Additional results from HA-mediated hemolysis of chicken red blood cells (cRBCs), competition assay with MAb C179 and mutational analysis suggest that the compounds bind in the stem region of the HA trimer and inhibit HA mediated fusion. Therefore, MBX2329 and MBX2546 represent new starting points for chemical optimization and have the potential to provide valuable future therapeutic options and research tools to study the HA mediated entry process.
PMID:
24198411
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24198411