Progress for dengue virus diseases. Towards the NS2B-NS3pro inhibition for a therapeutic-based approach.
Transmitted by the Aedes aegypti mosquito, the dengue virus is the etiological agent of dengue fever, dengue hemorrhagic fever and dengue shock syndrome, and, as such, is a significant factor in the high death rate found in most tropical and subtropical areas of the world. Dengue diseases are not only a health burden to developing countries, but pose an emerging problem worldwide. The immunopathological mechanisms appear to include a complex series of immune responses. A rapid increase in the levels of cytokines and chemical mediators during dengue disease plays a key role in inducing plasma leakage, shock and hemorrhagic manifestations. Currently, there are no vaccines available against dengue virus, although several tetravalent live-attenuated dengue vaccines are in clinical phases I or II, and prevention through vaccination has become a major priority on the agendas of the World Health Organization and of national ministries of health and military organizations. An alternative to vaccines is found in therapeutic-based approaches. Understanding the molecular mechanisms of viral replication has led to the development of potential drugs, and new molecular viral targets for therapy are emerging. The NS3 protease domain of the NS3 protein is responsible for processing the viral polyprotein and its inhibition is one of the principal aims of pharmacological therapy. This review is an overview of the progress made against dengue virus; in particular, it examines the unique properties--structural and functional--of the NS3 protease for the treatment of dengue virus infections by the inhibition of viral polyprotein processing.
Melino
Sonia
S
Department of Chemical Science and Technology, University of Rome Tor Vergata, Italy. melinos@uniroma2.it
Paci
Maurizio
M
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003715:Dengue / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D053059:Dengue Vaccines; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012697:Serine Endopeptidases / Q000378:metabolism*; D019595:Severe Dengue / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication; D014944:World Health Organization; D000085242:Viral Proteases
D000998:Antiviral Agents; D053059:Dengue Vaccines; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases