Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses

Abstract

Introduction Seven arenaviruses cause viral hemorrhagic fever in humans: the Old World arenaviruses Lassa and Lujo, and the New World Clade B arenaviruses Machupo (MACV), Junín (JUNV), Guanarito (GTOV), Sabiá (SABV), and Chapare (CHPV). All of these viruses are Risk Group 4 biosafety pathogens. MACV causes human disease outbreak with high case-fatality rates. To date, at least 1,200 cases with ≈200 fatalities have been recorded 1, 2. Areas covered This review summarizes available systems and technologies for the identification of antivirals against MACV, animal models for in vivo evaluation of novel inhibitors, present treatment of arenaviral diseases, overview of efficacious small molecules and other therapeutics reported to date, and strategies to identify novel inhibitors for anti-arenaviral therapy. Expert opinion New high-throughput approaches to quantitate infection rates of areaviruses, as well as viruses modified to carry reporter genes, will accelerate compound screens and drug discovery efforts. RNAi, gene expression profiling and proteomics studies will identify host targets for therapeutic intervention. New discoveries in the cell entry mechanism of MACV and other arenaviruses as well as extensive structural studies of arenaviral L and NP could facilitate the rational design of antivirals effective against all pathogenic New World arenaviruses.

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

“…JUNV is endemic in regions of Argentina and West Africa and is the cause of severe episodes of hemorrhagic fever with high mortality rates. The search for effective therapeutics to treat arenavirus infections, particularly those caused by Junin and Lassa viruses, has been an active area of research for many years (8,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). More recent efforts in the field of antiviral therapeutics for emerging RNA viruses have focused on identifying host factors or virus-host interactions, rather than solely viral proteins, as targets for novel antivirals (6, 8-13, 39, 40, 43, 44).…”

Pathology of Experimental Machupo Virus Infection, Chicava Strain, in Cynomolgus Macaques (Macaca fascicularis) by Intramuscular and Aerosol Exposure

“…The end of study for the IM-challenged macaques was 30 days postexposure; however, all macaques succumbed prior to or on day 21. For the aerosol studies, the study end point was extended to 35 Virus Isolation, Preparation, Plaque Assay, Exposure, and Sampling Scheme…”

“…19,35 MACV is the source agent of outbreaks of Bolivian hemorrhagic fever (BHF) in remote endemic regions of South America. BHF was first described during an outbreak of severe febrile disease in 1959 that occurred in a remote prairie region between Bolivia and Brazil.…”

Pathogenesis of Bolivian Hemorrhagic Fever in Guinea Pigs

“…7,[14][15][16][17][18][19]22 Between 1959 and 1962, 470 cases were reported in the northeast corner of Bolivia, and a second series of outbreaks transpired between 1962 and 1964, resulting in around 1000 cases and 180 deaths. 7,23 No cases of BHF were reported between 1976 and 1993, but an outbreak in 1994 consisting of 19 cases was the first in a recent string of sporadic outbreaks culminating in 20 cases in 2007 and more than 200 in 2008. 1,22,23 The overall case fatality rate has varied among outbreaks, but up to 30% of those infected with MACV die from it or complications related to infection.…”

“…1,23 Occupational exposure to aerosolized virus during grain harvesting is the most likely reason for this spike. 1,19,23 Infection can also occur between caregivers and afflicted patients from close contact, and caregiver transmission has been reported during more than 1 outbreak. 7,20 The incubation period for BHF in humans can vary from 5 to 21 days but generally is between 7 and 14 days.…”