Entry of influenza virus into the host cell is dependent on the fusion of the viral envelope with the endosomal membrane and is mediated by a low-pH-induced change of the viral hemagglutinin (HA) to a conformation that is fusogenic. A compound related to @entity70424 (180299) was identified that inhibits multicycle replication of influenza A/Kawasaki/86 (H1N1) virus in culture. Treatment of Madin-Darby @entity235 kidney (MDCK) cells with 180299 at 1 h before infection resulted in the inhibition of viral protein synthesis. Addition of 20 microgram of 180299/ml at 1 h p.i. had no effect, indicating that 180299 affects an early step of the influenza viral replication cycle. Genetic analysis of reassortants between sensitive and resistant viruses demonstrated that hemagglutinin (HA) conferred the 180299-resistant (180299(r)) phenotype. Twelve independent isolates of influenza A/Kawasaki/86 were selected for resistance to 180299, and sequence analysis revealed that each of these viruses contained @entity3689 substitutions in the HA. These mutations are dispersed throughout the HA primary @entity3689 sequence and cluster in one of two regions: the interface between HA1 and HA2 and in a region near the fusion domain of HA2. When compared with the parent virus, the pH-of-inactivation of the resistant mutants was increased by 0.3 to 0.6 pH unit, suggesting that the mutant HAs undergo the conformational change at an elevated pH. Fusion of @entity1 erythrocytes to MDCK cells infected with parent influenza A/Kawasaki/86 was inhibited by 180299 (0.1-10 microgram/ml) in a concentration-dependent manner, whereas fusion of erythrocytes to MDCK cells infected with 180299(r) mutants was not affected. These results suggest that 180299 interacts with the neutral pH conformation of influenza A HA and prevents the low-pH-induced change of HA to its fusogenic conformation.

Inhibition of influenza virus hemagglutinin-mediated membrane fusion by a compound related to XXXX .

@entity235 :: ('9615', 'Species') :: ['canine'] @entity1 :: ('9606', 'Species') :: ['human'] @entity70424 :: ('MESH:C002470', 'Chemical') :: ['podocarpic acid'] @entity3689 :: ('D000596', 'Chemical') :: ['amino acid']
@entity70424 :: (MESH:C002470,Chemical) :: ['podocarpic acid']
