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Novel inhibitors of influenza virus fusion: structure activity relationship and interaction with the viral hemagglutinin. (J Virol., abstract, edited)
10. J Virol. 2010 Feb 24. [Epub ahead of print]
Novel inhibitors of influenza virus fusion: structure activity relationship and interaction with the viral hemagglutinin.
Vanderlinden E, Goktas F, Cesur Z, Froeyen M, Reed ML, Russell CJ, Cesur N, Naesens L. - Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey; Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678.
A new class of N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide inhibitors of influenza virus hemagglutinin (HA)-mediated membrane fusion was identified that has a narrow and defined structure-activity relationship. In Madin-Darby canine kidney (MDCK) cells infected with different strains of human influenza virus A/H3N2, the lead compound 4c displayed a 50% effective concentration of 3-23 muM and an antiviral selectivity index of 10. No activity was observed for A/H1N1, A/H5N1, A/H7N2 and B viruses. The activity of 4c was reduced considerably when added 30 minutes or later post infection, indicating that 4c inhibits an early step in virus replication. 4c and its congeners inhibited influenza A/H3N2 virus-induced erythrocyte hemolysis at low pH. 4c-resistant virus mutants, selected in MDCK cells, contained either a single D112N change in the HA2 subunit of the viral HA, or a combination of three substitutions, i.e. R220S (in HA1) and E57K (in HA2), and an A-T substitution at position 43 or 96 of HA2. The mutants showed similar efficiency for receptor binding and replication as wild-type virus, yet displayed an increased pH of erythrocyte hemolysis. In polykaryon assays with cells expressing single mutant HA proteins, the E57K, A96T and D112N mutations resulted in 4c resistance, and the HA proteins containing R220S, A96T and D112N mutations displayed an increased fusion pH. Molecular modeling identified a binding cavity for 4c involving arginine-54 and glutamic acid-57 in the HA2 subunit. Our studies with the new fusion inhibitor 4c confirm the importance of this HA region in the development of influenza virus fusion inhibitors.
PMID: 20181685 [PubMed - as supplied by publisher]
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10. J Virol. 2010 Feb 24. [Epub ahead of print]
Novel inhibitors of influenza virus fusion: structure activity relationship and interaction with the viral hemagglutinin.
Vanderlinden E, Goktas F, Cesur Z, Froeyen M, Reed ML, Russell CJ, Cesur N, Naesens L. - Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey; Division of Virology, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678.
A new class of N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide inhibitors of influenza virus hemagglutinin (HA)-mediated membrane fusion was identified that has a narrow and defined structure-activity relationship. In Madin-Darby canine kidney (MDCK) cells infected with different strains of human influenza virus A/H3N2, the lead compound 4c displayed a 50% effective concentration of 3-23 muM and an antiviral selectivity index of 10. No activity was observed for A/H1N1, A/H5N1, A/H7N2 and B viruses. The activity of 4c was reduced considerably when added 30 minutes or later post infection, indicating that 4c inhibits an early step in virus replication. 4c and its congeners inhibited influenza A/H3N2 virus-induced erythrocyte hemolysis at low pH. 4c-resistant virus mutants, selected in MDCK cells, contained either a single D112N change in the HA2 subunit of the viral HA, or a combination of three substitutions, i.e. R220S (in HA1) and E57K (in HA2), and an A-T substitution at position 43 or 96 of HA2. The mutants showed similar efficiency for receptor binding and replication as wild-type virus, yet displayed an increased pH of erythrocyte hemolysis. In polykaryon assays with cells expressing single mutant HA proteins, the E57K, A96T and D112N mutations resulted in 4c resistance, and the HA proteins containing R220S, A96T and D112N mutations displayed an increased fusion pH. Molecular modeling identified a binding cavity for 4c involving arginine-54 and glutamic acid-57 in the HA2 subunit. Our studies with the new fusion inhibitor 4c confirm the importance of this HA region in the development of influenza virus fusion inhibitors.
PMID: 20181685 [PubMed - as supplied by publisher]
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