Identification and characterization of nonsubstrate based inhibitors of the essential dengue and West Nile virus proteases.
The 72 known members of the flavivirus genus include lethal human pathogens such as Yellow Fever, West Nile, and Dengue viruses. There is at present no known chemotherapy for any flavivirus and no effective vaccines for most. A common genomic organization and molecular mechanisms of replication in hosts are shared by flaviviruses with a viral serine protease playing a pivotal role in processing the viral polyprotein into component polypeptides, an obligatory step in viral replication. Using the structure of the dengue serine protease complexed with a protein inhibitor as a template, we have identified five compounds, which inhibit the enzyme. We also describe parallel inhibitory activity of these compounds against the West Nile virus Protease. A few of the compounds appear to provide a template for design of more potent and specific inhibitors of the dengue and West Nile virus proteases. Sequence similarities among flaviviral proteases suggests that such compounds might also possibly inhibit other flaviviral proteases.
Ganesh
Vannakambadi K
VK
Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, CBSE 100, 1530, 3rd Avenue South, Birmingham, AL 35294-4400, USA.
Muller
Nik
N
Judge
Ken
K
Luan
Chi-Hao
CH
Padmanabhan
Radhakrishnan
R
Murthy
Krishna H M
KH
D000595:Amino Acid Sequence; D003716:Dengue Virus / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014902:West Nile virus / Q000201:enzymology*
D011480:Protease Inhibitors; D010447:Peptide Hydrolases