Dengue virus

What is Dengue virus (DENV)?

Dengue virus (DENV) belongs to the genus Flaviviridae and is transmitted to humans by Aedes mosquitoes, mainly Aedes Egypt. Dengue virus can be classified into four types: DENV-1, DENV-2, DENV-3 and DENV-4. Dengue virus infection is the leading cause of disease in tropical and subtropical regions, with an estimated 50 million infections each year and more than 2.5 billion people at risk of infection.

Mature DENV virions are characterized by a smooth surface with a diameter of about 50 nM, while immature virions are 60 nm in diameter with spikes on the surface. The genome encodes 3 structural proteins (capsid (C, 100 amino acids (aa)), anterior membrane/membrane (prM/M, 75 aa (and envelope (E, 495 aa)), and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Structural proteins form the building blocks of DENV virions, while nonstructural proteins are involved in RNA replication.

Fig.1 The genes of the Dengue virus. Fig.1 Genome structure of Dengue virus. (Siritt Maria Eugenia Guzman, et al., 2010)

How did the Dengue virus spread?

After the Aedes mosquito bites a dengue fever patient or a latently infected person, the dengue virus generally needs to multiply in the body of the Aedes mosquito after 8~10 days, and the dengue virus can be transmitted to healthy people through the bite. However, it is important to note that the dengue virus is not transmitted directly from person to person.

Dengue virus diseases

Latent infection, dengue fever and dengue hemorrhagic fever may occur after the dengue virus infects the human body. Clinically, dengue fever can be divided into typical, mild and severe, and in patients with severe dengue, the mortality rate can be as high as 50%. Typical dengue fever has the following symptoms: fever, which usually begins suddenly, and the body temperature rises rapidly above 39 degrees Celsius, usually lasting 2 to 7 days. The rash appears 2 to 5 days after onset, initially on the palms, soles of the feet, or trunk and abdomen, and gradually extends to the neck and limbs. Bleeding occurs 5 to 8 days after onset, and about half of cases may have bleeding of varying degrees from different locations. In addition, the lymph nodes throughout the body may be mildly enlarged with mild tenderness.

Dengue virus test

DENV infection can be diagnosed directly by testing for viral components in serum or indirectly by serological methods. The sensitivity of the various methods depends on the duration of the disease and at what stage of the course the patient is being evaluated. Detection of viral nucleic acids or viral antigens is more specific, but more cumbersome and expensive. Serologic testing is less specific, but it is easier to perform and less expensive.

IgM can be detected as early as 4 days after onset by lateral flow immunoassay or IgM antibody capture ELISA. In addition, isolation of the virus (culture method) can also confirm DENV infection, and in general, culture methods are not necessary for clinical diagnosis, as culture results are usually not available within a clinically meaningful time frame. Immunohistochemical staining can detect DENV protein in tissue samples, and the detection rate appears to be higher in liver tissue.

Dengue virus treatment

Dengue virus vaccines

At present, there are three main dengue vaccines in the leading state of research and development, namely Dengvaxia (CYD-TDV) (Sanofi Pasteur of France), Qdenga (TAK-003) (Takeda Pharmaceutical of Japan), and TV003 (National Institutes of Health of United States).

Denvaxia is currently the only vaccine licensed in multiple countries and the first to be included in the World Health Organization's prequalification vaccine list. However, the vaccine has been observed to be less effective and less effective in children and dengue patients, and it also increases the risk of severe dengue fever in people who have not been infected with dengue after vaccination.

The results of the Phase 3 clinical trial of TAK-003 (DENVax) have been released, which can produce a good immune effect and reduce the incidence of severe disease. The World Health Organization (WHO) announced on 15 May 2024 that TAK-003 (DENVax) vaccine has been added to the WHO Prequalification List of vaccines recommended for children aged 6 to 16 years in areas with high levels of dengue virus transmission. The vaccine is given in two doses, 3 months apart.

The phase III clinical trial of TV-003/TV-005 (LATV) vaccine showed that the vaccine can produce better immune effects and reduce the incidence of severe disease.

Dengue virus medicine therapy

The development of small molecule anti-dengue drugs has been a slow process. To date, there are only four small-molecule anti-dengue drugs: Chloroquine (NCT00849602), Celgosivir (NCT01619969), Balapiravir (NCT01096576), and UV-4B(NCT02061358). NCT02696291) has entered the clinical stage.

The development of novel DENV inhibitors remains urgent. Over the past five years, antiviral inhibitors have been designed to target essential proteins and host factors in the dengue virus life cycle. The targets include NS3/NS2B protease, NS3 helicase E protein, and NS5 RNA-dependent RNA polymerase (RdRp).

NS3/2B Protease Inhibitors

NS3/2Bpro inhibitors need to compete with substrate peptides with P1 and P2 positions, which are essential Arg responses. α-Ketoamide and tri/tetrapeptide (three or four are found to contain the remaining peptide containing an electrophilic group to interact with the catalytic pocket. NS2B/NS3-IN-2 is a potent covalent inhibitor of dengue virus NS2B/NS3 with an IC₅₀ of 6.0 nM, NS2B/NS3-IN-2 is non-cytotoxic and significantly improves cell viability. DV-B-120 is a competitive inhibitor of dengue virus (DENV), inhibits DENV-1, DENV-2, DENV-3 and DENV-4 with IC₅₀ of 5.35, 7.39, 10.49 and 8.58 μM by inhibiting the NS2B-NS3 protease.

NS3 helicase inhibitors

The benzoxazole inhibitor ST-610 is reported by Byrd, which is a potent inhibitor of DE NV2 (EC50=0.272 μM). The compound is non-toxic to DENV1-4 in cell culture and is mutagenic in the Ames assay. The A263T mutation mapped on a basic patch within the NS3heli channel correlates with susceptibility to ST-610. Another report by Basavannacharya et al. A method for the analysis of NS3heli molecular beacon helicase was constructed. By screening a library of 1600 compounds, they determined that Surumin was a potent, noncompetitive inhibitor.

RdRp inhibitors

In order to inhibit the DENV virus RdRp, several methods have been introduced: nucleosides or their analogues that terminate RNA replication. Non-nucleosides that block allosteric sites and affect RdRp activity (e.g., N-sulfonylanthraceneamide derivatives, sofosbuvir, and HeE1-2Tyr, 66E2) and metal chelators (DMB220) that target essential ions in the catalytic process.

Inhibitors that target other viral proteins

A team of researchers from Novartis reported the activity of spiropyrrolopyridone against NS4B. The first is a racemate screened from DENV2 replicon analysis. After separating the enantiomers, they found compounds with better activity in the R enantiomers (1a). Compound 1a inhibits DENV2 and DENV3, but does not have the same effect on DENV1 and DENV4.

References

Kuhn, Richard J., et al., Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108.5 (2002): 717-725.
Sinha, Saumya, et al., Dengue virus pathogenesis and host molecular machineries. Journal of Biomedical Science 31.1 (2024): 43.
Martina, Byron EE, et al., Dengue virus pathogenesis: an integrated view. Clinical microbiology reviews 22.4 (2009): 564-581.
Tian, Yu-Shi, et al., Dengue virus and its inhibitors: a brief review. Chemical and Pharmaceutical Bulletin 66.3 (2018): 191-206.
Siritt, Maria Eugenia Guzman, et al., Dengue: a continuing global threat. Nature Reviews Microbiology 8.12 (2010): S7-S16.

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