Efficacy of novel hemagglutinin-neuraminidase inhibitors BCX 2798 and BCX 2855 against human parainfluenza viruses in vitro and in vivo.
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 (HN) protein. The compounds were highly effective in inhibiting hemagglutinin (HA) and neuraminidase (NA) activities and the growth of hPIV-1, hPIV-2, and hPIV-3 in LLC-MK(2) cells. The concentrations required to reduce the activity to 50% of that of a control ranged from 0.1 to 6.0 micro M in HA inhibition assays and from 0.02 to 20 micro M in NA inhibition assays. The concentrations required to inhibit virus replication to 50% of the level of the control ranged from 0.7 to 11.5 micro M. BCX 2798 and BCX 2855 were inactive against influenza virus HA and NA and bacterial NA. In mice infected with a recombinant Sendai virus whose HN gene was replaced with that of hPIV-1 [rSV(hHN)], intranasal administration of BCX 2798 (10 mg/kg per day) and of BCX 2855 (50 mg/kg per day) 4 h before the start of infection resulted in a significant reduction in titers of virus in the lungs and protection from death. Treatment beginning 24 h after the start of infection did not prevent death. Together, our results indicate that BCX 2798 and BCX 2855 are effective inhibitors of parainfluenza virus HN and may limit parainfluenza virus infections in humans.
Alymova
Irina V
IV
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Taylor
Garry
G
Takimoto
Toru
T
Lin
Tsu-Hsing
TH
Chand
Pooran
P
Babu
Y Sudhakara
YS
Li
Chenghong
C
Xiong
Xiaoping
X
Portner
Allen
A
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006388:Hemagglutinins / Q000187:drug effects*; D006603:Hexuronic Acids / Q000494:pharmacology*; D006801:Humans; D018374:LLC-PK1 Cells; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D010222:Parainfluenza Virus 1, Human / Q000187:drug effects*; D010223:Parainfluenza Virus 2, Human / Q000187:drug effects*; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects*; D018184:Paramyxoviridae Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D011994:Recombinant Proteins; D029082:Sendai virus / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D014760:Viral Fusion Proteins / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
C486445:4-dichloromethanesulfonylamino-2,3-didehydro-2,3,4,5-tetradeoxyglycerogalacto-2-nonulopyranosic acid; C486444:4-zido-5-isobutyrylamino-2,3-didehydro-2,3,4,5-tetradeoxyglycerogalacto-2-nonulopyranosic acid; D000998:Antiviral Agents; D001386:Azides; D004791:Enzyme Inhibitors; D006388:Hemagglutinins; D006603:Hexuronic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; D014760:Viral Fusion Proteins; D009439:Neuraminidase