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ML336: Development of Quinazolinone-Based Inhibitors Against Venezuelan Equine Encephalitis Virus (VEEV).

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Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2012 Dec 17 [updated 2013 Nov 07].

Excerpt

Alphaviruses like Venezuelan Equine Encephalitis Virus (VEEV) are enveloped, positive-sense, single stranded RNA viruses that are geographically widely distributed. They are arthropod-borne viruses that are known to cause rash, arthritis, encephalitis, and death in humans. Of the more than 30 alphavirus pathogens known, about a third contributes to human disease, and currently there are no FDA approved treatments available for any of them. A renewed interest to find effective therapeutic leads for development has emerged due to the lack of effective countermeasures for these pathogens, the increased incidence of their prevalence with global climate changes, and the ease with which they can and have been weaponized as biological threats. VEEV vaccines to date show insufficient efficacy or adverse side effects that limit their use, and disclosed literature compounds possess weak anti-VEEV potency and/or involve host-mediated mechanisms of action, contributing to off-target effects. The high throughput-screen of the MLSMR revealed a subset of scaffolds that inhibited a VEEV-induced cytopathic effect in the low micromolar range. Medicinal chemistry optimization resulted in the development of ML336, a first-in-class probe that inhibited a VEEV-induced cytopathic effect in three strains of the virus (TC-83, V3526, and Trinidad donkey) in the low nanomolar range without showing cytotoxicity (> 50 μM, selectivity index > 1500). Furthermore, ML336 dramatically reduced viral titer (> 7.2 log) below a 1 μM compound concentration and features a favorable in vitro pharmacokinetic profile which includes moderate blood-brain barrier permeability. Importantly, ML336 appears to target the VEEV non-structural protein 2 (nsP2) which is necessary for transcription and replication of viral RNA. This finding alone distinguishes ML336 from all other compounds described to date, and in combination with its overall profile, makes it an ideal candidate for further in vivo development.

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