Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses.

08:00 EDT 7th April 2019 | BioPortfolio

Summary of "Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses."

Currently, there are no licensed human vaccines or antivirals for treatment of or prevention from infection with encephalitic alphaviruses. Because epidemics are sporadic and unpredictable, and endemic disease is common but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we have continued development of ML336 to deliver a molecule with prophylactic and therapeutic potential that could be relevant for use in natural epidemics or deliberate release scenario for Venezuelan equine encephalitis virus (VEEV). We report findings from in vitro assessments of four analogs of ML336, and in vivo screening of three of these new derivatives, BDGR-4, BDGR-69 and BDGR-70. The optimal dosing for maximal protection was observed at 12.5 mg/kg/day, twice daily for 8 days. BDGR-4 was tested further for prophylactic and therapeutic efficacy in mice challenged with VEEV Trinidad Donkey (TrD). Mice challenged with VEEV TrD showed 100% and 90% protection from lethal disease when treated at 24 and 48 h post-infection, respectively. We also measured 90% protection for BDGR-4 in mice challenged with Eastern equine encephalitis virus. In additional assessments of BDGR-4 in mice alone, we observed no appreciable toxicity as evaluated by clinical chemistry indicators up to a dose of 25 mg/kg/day over 4 days. In these same mice, we observed no induction of interferon. Lastly, the resistance of VEEV to BDGR-4 was evaluated by next-generation sequencing which revealed specific mutations in nsP4, the viral polymerase.


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This article was published in the following journal.

Name: Antiviral research
ISSN: 1872-9096


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Medical and Biotech [MESH] Definitions

A form of arboviral encephalitis endemic to Central America and the northern latitudes of South America. The causative organism (ENCEPHALITIS VIRUS, VENEZUELAN EQUINE) is transmitted to humans and horses via the bite of several mosquito species. Human viral infection may be asymptomatic or remain restricted to a mild influenza-like illness. Encephalitis, usually not severe, occurs in a small percentage of cases and may rarely feature SEIZURES and COMA. (From Joynt, Clinical Neurology, 1996, Ch26, pp9-10)

A form of arboviral encephalitis (primarily affecting equines) endemic to eastern regions of North America. The causative organism (ENCEPHALOMYELITIS VIRUS, EASTERN EQUINE) may be transmitted to humans via the bite of AEDES mosquitoes. Clinical manifestations include the acute onset of fever, HEADACHE, altered mentation, and SEIZURES followed by coma. The condition is fatal in up to 50% of cases. Recovery may be marked by residual neurologic deficits and EPILEPSY. (From Joynt, Clinical Neurology, 1996, Ch26, pp9-10)

A species of ALPHAVIRUS that is the etiologic agent of encephalomyelitis in humans and equines. It is seen most commonly in parts of Central and South America.

A species of ALPHAVIRUS causing encephalomyelitis in Equidae and humans. The virus ranges along the Atlantic seaboard of the United States and Canada and as far south as the Caribbean, Mexico, and parts of Central and South America. Infections in horses show a mortality of up to 90 percent and in humans as high as 80 percent in epidemics.

A mosquito-borne encephalitis caused by the Japanese B encephalitis virus (ENCEPHALITIS VIRUS, JAPANESE) occurring throughout Eastern Asia and Australia. The majority of infections occur in children and are subclinical or have features limited to transient fever and gastrointestinal symptoms. Inflammation of the brain, spinal cord, and meninges may occur and lead to transient or permanent neurologic deficits (including a POLIOMYELITIS-like presentation); SEIZURES; COMA; and death. (From Adams et al., Principles of Neurology, 6th ed, p751; Lancet 1998 Apr 11;351(9109):1094-7)

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