Human parainfluenza viruses are important respiratory tract pathogens, especially of children. However, no vaccines or specific therapies for infections caused by these viruses are currently available. In the present study we characterized the efficacy of the novel parainfluenza virus inhibitors BCX 2798 and BCX 2855, which were designed based on the three-dimensional structure of the hemagglutinin-neuraminidase ( The human parainfluenza viruses (hPIVs), which are members of the Paramyxoviridae family, are important respiratory tract pathogens of infants, children, and young adults. Four different types of hPIVs have been identified, all of which cause a spectrum of illnesses of the upper and lower respiratory tracts of children (20,23,28). Annual epidemics of parainfluenza virus infections continue to occur, and the resources required to deal with these infections cost millions of dollars annually (14).At this time there are no effective vaccines or specific therapies to control parainfluenza virus infections.Parainfluenza virus infection requires the hemagglutininneuraminidase (HN) protein, a major surface glycoprotein that has functional sites for cell attachment and neuraminidase (NA) activity (5). HN recognizes sialic acid-containing receptors on the cell surface, and this recognition allows the virus to bind to target cells (22). HN also acts as an NA, removing sialic acid from virus particles and thus preventing self-aggregation of virus and promoting efficient spread of virus (21). In addition, HN promotes the activity of the fusion (F) protein, thereby allowing the virus to penetrate the cell surface (32, 43). The F protein is another major glycoprotein that is located on the surface of the virion and plays an important role in parainfluenza virus replication. Early in infection, the F glycoprotein mediates penetration of the host cell by fusion of the viral envelope to the plasma membrane. At a late stage of infection, the protein mediates fusion of the infected cells with contiguous uninfected cells, leading to the formation of a syncytium and the spread of infection in the local area. Many studies have shown that a type-specific functional interaction between HN and F is required for efficient membrane fusion (15, 16). The binding of HN protein to its receptor induces the conformational change of residues near the hydrophobic surface of the HN protein and, probably, this change triggers the activation of the F protein, which initiates membrane fusion (34).The efficient inhibition of the HN protein has to block cell attachment, fusion promotion, and NA activities, thereby preventing both infection by virus and virus spreading. Because of the key role of HN in the infectivity of parainfluenza virus, attention was concentrated on the development of selective inhibitors for the prophylaxis and treatment of hPIV infections. The extensive crystallographic and biochemical studies of the HN protein of Newcastle disease virus (NDV) (8, 33) yielded a high level of structural information for the design of new d...