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Carbohydrate-related inhibitors of dengue virus entry.

ABSTRACT: Dengue virus (DENV), which is transmitted by Aedes mosquitoes, causes fever and hemorrhagic disorders in humans. The virus entry process mediated through host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue disease. Therefore, elucidation of the molecular mechanisms underlying virus entry is essential for an understanding of dengue pathology and for the development of effective new anti-dengue agents. DENV binds to its receptor molecules mediated through a viral envelope (E) protein, followed by incorporation of the virus-receptor complex inside cells. The fusion between incorporated virus particles and host endosome membrane under acidic conditions is mediated through the function of DENV E protein. Carbohydrate molecules, such as sulfated glycosaminoglycans (GAG) and glycosphingolipids, and carbohydrate-recognition proteins, termed lectins, inhibit virus entry. This review focuses on carbohydrate-derived entry inhibitors, and also introduces functionally related compounds with similar inhibitory mechanisms against DENV entry.

SUBMITTER: Hidari KI

PROVIDER: S-EPMC3640517 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Carbohydrate-related inhibitors of dengue virus entry.

Hidari Kazuya I P J KI Abe Tomoko T Suzuki Takashi T

Viruses 20130206 2

Dengue virus (DENV), which is transmitted by Aedes mosquitoes, causes fever and hemorrhagic disorders in humans. The virus entry process mediated through host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue disease. Therefore, elucidation of the molecular mechanisms underlying virus entry is essential for an understanding of dengue pathology and for the development of effective new anti-dengue agents. DENV binds to its receptor molecules mediated ...[more]

PMID: 23389466

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Project description:BackgroundDengue is the most prevalent arthropod-borne viral human disease in tropical and subtropical regions, caused by four dengue virus (DENV) serotypes. In spite of the increasing global incidence, no specific antiviral therapy is available. Cells of the mononuclear phagocyte lineage are the main targets either for direct antibody (Ab)-independent or Ab-mediated human DENV infection, usually associated to the severe forms of disease. Since the virus entry may be a convenient therapeutic alternative, this study aimed to investigate the mode of DENV internalization into myeloid cells in the absence and presence of DENV Ab and evaluate the inhibitory activity of diverse biochemical inhibitors of endocytosis.Methodology/principal findingsBy infectivity assays and quantitative RT-PCR determinations, it was demonstrated that DENV-2 entry into U937 and K562 cells in the absence of Ab was highly inhibited by the early treatment with ammonium chloride, chlorpromazine and dynasore, but it was not affected by methyl-?-cyclodextrin, indicating that DENV-2 utilizes a low pH-dependent, clathrin- and dynamin-mediated endocytic infectious pathway for the direct entry into both human myeloid cells. To study the Ab-mediated entry of DENV, the experimental conditions for enhancement of infection were established by inoculating immune complexes formed with DENV-2 and the Ab 2H2 or 3H5. The internalization of DENV-2-2H2 or DENV-2-3H5 complexes in both myeloid cells was also dependent on acid pH and dynamin but a differential requirement of the clathrin-mediated endocytic route was observed depending on the Fc?R involved in the complex uptake: the infection through Fc?RII was dependent on clathrin-coated vesicles whereas the internalization pathway mediated by Fc?RI was independent of clathrin. This property was not serotype-specific.Conclusions/significanceDENV entry into myeloid cells in the absence or presence of Ab can be blocked by diverse biochemical inhibitors affecting the cellular factors involved in endocytosis. The identification of the virus-host interactions involved in virus penetration may allow the finding of host-targeted antivirals widely active against diverse pathogenic flaviviruses with similar requirements for virus entry.

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Carbohydrate-related inhibitors of dengue virus entry.

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Carbohydrate-related inhibitors of dengue virus entry.

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