Benzamidine ML336 inhibits plus and minus strand RNA synthesis of Venezuelan equine encephalitis virus without affecting host RNA production

Publication date: Available online 6 December 2019Source: Antiviral ResearchAuthor(s): Andrew M. Skidmore, Robert S. Adcock, Colleen B. Jonsson, Jennifer E. Golden, Dong-Hoon ChungAbstractVenezuelan equine encephalitis virus (VEEV) is an alphavirus that is endemic to the Americas. VEEV outbreaks occur periodically and cause encephalitis in both humans and equids. There are currently no therapeutics or vaccines for treatment of VEEV in humans. Our group has previously reported on the development of a benzamidine VEEV inhibitor, ML336, which shows potent antiviral activity in both in vitro and in vivo models of infection. In cell culture experiments, ML336 inhibits viral RNA synthesis when added 2–4 h post-infection, and mutations conferring resistance occur within the viral nonstructural proteins (nsP2 and nsP4). We hypothesized that ML336 targets an activity of the viral replicase complex and inhibits viral RNA synthesis. To test this hypothesis, we employed various biochemical and cellular assays. Using structural analogues of ML336, we demonstrate that the cellular antiviral activity of these compounds correlates with their inhibition of viral RNA synthesis. For instance, the IC50 of ML336 for VEEV RNA synthesis inhibition was determined as 1.1 nM, indicating potent anti-RNA synthesis activity in the low nanomolar range. While ML336 efficiently inhibited VEEV RNA synthesis, a much weaker effect was observed against the Old World alphavirus Chikungunya virus (IC50...
Source: Antiviral Therapy - Category: Virology Source Type: research

Related Links:

Abstract Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is endemic to the Americas. VEEV outbreaks occur periodically and cause encephalitis in both humans and equids. There are currently no therapeutics or vaccines for treatment of VEEV in humans. Our group has previously reported on the development of a benzamidine VEEV inhibitor, ML336, which shows potent antiviral activity in both in vitro and in vivo models of infection. In cell culture experiments, ML336 inhibits viral RNA synthesis when added 2-4 h post-infection, and mutations conferring resistance occur within the viral nonstructural ...
Source: Antiviral Research - Category: Virology Authors: Tags: Antiviral Res Source Type: research
We describe the unexpected binding of S-layer to cells devoid of DC-SIGN but also confirm that the presence of DC-SIGN was essential for S-layer’s antiviral activity. S-layer protein exerted its antiviral effect with different kinetics than mannan, a known viral inhibitor that also acts on DC-SIGN (Yu et al., 2017). Together our results suggest that inhibition of viral entry by S-layer occurs via a novel S-layer/DC-SIGN interaction. Materials and Methods Isolation of S-Layer Proteins S-layer proteins were extracted from overnight cultures of L. acidophilus ATCC 4356 cells grown in MRS medium at 37°C by using 6...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Conclusion and Perspectives Arbovirus infections, such as CHIKV, have been growing worldwide and are becoming a major public health problem, especially in immuno-compromised classes such as children and the elderly. CHIKV is dangerous since it can cause arthritis, fever and other impairments, making it necessary to seek new ways to counter the proliferation of this virus. Knowing the vector’s competence is fundamentally important, including an understanding of the vector virus interaction and the modulation of this interaction. Despite advances in the knowledge of mosquito competence in the transmission of CHIKV, li...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
In this study, we were able to demonstrate that our measure for mosquito-borne viral suitability is informative in the context of Myanmar, despite the lack of ento-epidemiological datasets with high spatio-temporal resolution. By estimating suitability through climate variables and known ento-epidemiological parameters, we were able to project mosquito-born virus (MBV) suitability at the district level, a resolution for which epidemiological data and mosquito abundance measures are not generally available. Here, we discuss the national and subnational public health and control implications for MBVs in the context of our pr...
Source: PLOS Currents Outbreaks - Category: Epidemiology Authors: Source Type: research
LITFL • Life in the Fast Lane Medical Blog LITFL • Life in the Fast Lane Medical Blog - Emergency medicine and critical care medical education blog aka Tropical Travel Trouble 010 Peer Reviewer: Dr Jennifer Ho, ID physician QLD, Australia You are an ED doc working in Perth over schoolies week. An 18 yo man comes into ED complaining of fever, rash a “cracking headache” and body aches. He has just hopped off the plane from Bali where he spent the last 2 weeks partying, boozing and running amok. He got bitten by “loads” of mosquitoes because he forgot to take insect repellent. On e...
Source: Life in the Fast Lane - Category: Emergency Medicine Authors: Tags: Clinical Cases Tropical Medicine arthralgia dengue fever rash Source Type: blogs
Publication date: Available online 5 July 2018Source: Antiviral ResearchAuthor(s): Lindsay Lundberg, Ashwini Brahms, Idris Hooper, Brian Carey, Shih-Chao Lin, Bibha Dahal, Aarthi Narayanan, Kylene Kehn-HallAbstractThe New World alphaviruses –Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, and WEEV respectively) – cause a febrile disease that is often lethal in equines and children and leads to long-term neurological sequelae in survivors. Endemic to the Americas, epizootic outbreaks of the three viruses occur sporadically in the continental United States. All three viruses aerosolize r...
Source: Antiviral Therapy - Category: Virology Source Type: research
Abstract The New World alphaviruses -Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, and WEEV respectively) - cause a febrile disease that is often lethal in equines and children and leads to long-term neurological sequelae in survivors. Endemic to the Americas, epizootic outbreaks of the three viruses occur sporadically in the continental United States. All three viruses aerosolize readily, replicate to high titers in cell culture, and have low infectious doses. Additionally, there are no FDA-approved vaccines or therapeutics for human use. To address the therapeutic gap, a high throughp...
Source: Antiviral Research - Category: Virology Authors: Tags: Antiviral Res Source Type: research
Abstract Being the largest archipelago country in the world, with a tropical climate and a unique flora and fauna, Indonesia habitats one of the most diverse biome in the world. These characteristics make Indonesia a popular travel destination, with tourism numbers increasing yearly. These characteristics also facilitate the transmission of zoonosis and provide ideal living and breading circumstances for arthropods, known vectors for viral diseases. A review of the past 10 years of literature, reports of the Ministry of Health, Republic of Indonesia and ProMED-mail shows a significant increase in dengue infection ...
Source: Critical Reviews in Microbiology - Category: Microbiology Authors: Tags: Crit Rev Microbiol Source Type: research
In conclusion, as millions of people continue to explore augmented reality games such as Pokémon Go each day, it will be important for public health officials and others to think creatively about how to minimize risks and maximize opportunities associated with this fundamentally new and distinct activity. Competing Interest Statement The authors have declared that no competing interests exist. Ethics Statement The individuals in this manuscript have given written informed consent (as outlined in PLOS consent form) to publish these case details. Corresponding Author Rachel Oidtman, E-mail: roidtman@nd.edu Alex Pe...
Source: PLOS Currents Outbreaks - Category: Epidemiology Authors: Source Type: research
CONCLUSIONS ZIKV epidemic poses new challenges to public health, our knowledge about this virus is incipient. In Brazil, a relationship between ZIKV and microcephaly has been mentioned since November 20157 which has not been reported in ZIKV outbreaks in other areas of the world. Several research groups are working on this topic. Guillain Barré Syndrome also has been reported as a complication of ZIKV; however, there are still many questions unanswered regarding the complications caused by this virus. Provide information to the population, following recommendations and preventive measures, taking actions to reduce...
Source: PLOS Currents Outbreaks - Category: Epidemiology Authors: Source Type: research
More News: Antiviral Therapy | Chikungunya | Encephalitis | Endemics | Nanotechnology | Outbreaks | Vaccines | Venezuela Health | Virology