Prophylactics/Therapeutics for treating Flaviviruses.

Flaviviruses such as Dengue virus (DENV), Yellow Fever virus (YFV) and West Nile virus (WNV) are significant human pathogens [1].

Both DENV and WNV can be transmitted by mosquitoes resulting in infection and disease. While DENV affects millions of people, there are currently no vaccines or approved specific prophylactics/therapeutics available for these viral infections.  

Dengue (DENV), is a mosquito-borne viral disease that can induce hemorrhagic fever with high mortality rates in those infected. DENV results in an estimated 50 to 100 million human infections, 500,000 hospitalizations, and 24,000 deaths per year [2]. Of prime concern in DENV vaccine development is the fact that an individual with incomplete immunization (against all 4 serotypes) may be sensitized to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) - potentially life-threatening conditions [3].

WNV is also transmitted by mosquitos and outbreaks of disease have been reported in each of the 48 contiguous United States, with ~24,000 human cases of WNV diagnosed between 1999 and 2006 [4]. In 2010, the CDC recorded only 1,021 WNV cases in the US resulting in 57 deaths  [5]. However, the number of reported infections may represent a very small percentage of all cases since as many as 730,000 infections may have been undiagnosed (based on detection of WNV RNA in the blood supply [6]).

Since there are currently no vaccines or approved therapeutic options available for flavivirus infections in humans, safe and effective therapeutics are urgently needed.

AnaViRx has identified a potent and safe lead candidate

AnaViRx compounds have demonstrated potency against WNV in cell-based infectivity assays. In a WNV CPE assay, we have identified a molecule that shows an EC50 of 450nM. The cytotoxicity of the compound (CC50) was greater then 100uM - suggesting the compound has an excellent safety index or SI50 (SI50=CC50/EC50; i.e. the SI50 would be >220). The compound is bioavailable when administered orally to animals and exhibits an excellent safety profile (LD50 >1.5g/Kg in mice). Based on this scaffold we have identified additional structures for evaluation that are predicted (through molecular modeling) to exhibit higher affinity to their expected target.

The small molecules based on the novel pharmacophore will be expected to provide a number of advantages in treating viral diseases:

1. They exhibit better stability at room temperature than biological agents – making distribution and stockpiling easier

2. They are orally available – allowing ease of administration

3. They will not suffer from the potential sensitization issues of vaccines (increasing the chances of hemorrhagic fever in subsequent DENV infections)

4. The compound is expected to be relatively inexpensive to manufacture  – allowing a commercial opportunity in economically challenged regions where these diseases are endemic.

Rational design, manufacture and testing of small molecules based on the high affinity pharmacophore starting point is providing valuable information about structural requirements for inhibition of flavivirus infection.

Integration of this information into molecular models is allowing further prediction and validation of more potent inhibitors - providing an excellent starting point for future therapeutic development.

 

REFERENCES

[1]. Burke, D. S., and T. P. Monath. (2001). “Flaviviruses,” p. 1043–1126. InD. M.Knipe, P. M. Howley, D. E. Griffin, et al. (ed.), Fields virology, 4th ed., vol. 1. Lippincott William & Wilkins, Philadelphia, Pa.

[2] Gubler, D., G. Kuno, and L. Markoff. (2007). “Flaviviruses”, p. 1153–1253. InD. M. Knipe and P. M. Howley (ed.), Fields virology, vol. 1, 5th ed. Lippincott William & Wilkins, Philadelphia, PA.

[3] Whitehead, S. S., J. E. Blaney, A. P. Durbin, and B. R. Murphy. (2007). “Prospects for a dengue virus vaccine.” Nat. Rev. Microbiol. 5:518–528.

[4] Granwehr, B. P., et al., (2004). “West Nile virus: where are we now?” Lancet Infect. Dis. 4:547–556.           

[5] CDC Table on WNV infection in the US. http://www.cdc.gov/ncidod/dvbid/westnile/surv&controlCaseCount10_detailed.htm

[6] Busch, M. P., et al., (2005). “Screening the blood supply for West Nile virus RNA by nucleic acid amplification testing.” N. Engl. J. Med. 353:460–467.

 

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