RMP has been shown to inhibit the activity of inosine monophosphate dehydrogenase (IMPDH), a catalyst in the synthesis of guanosine triphosphate (GTP), resulting in the disruption of critical viral replication steps [42,43,44,45]

RMP has been shown to inhibit the activity of inosine monophosphate dehydrogenase (IMPDH), a catalyst in the synthesis of guanosine triphosphate (GTP), resulting in the disruption of critical viral replication steps [42,43,44,45]. into clinical trials is critical to continue addressing this neglected tropical disease. genus in the family, is the causative agent of Lassa fever (LF). LASV was originally isolated and described in 1969 after a missionary nurse in Lassa, Nigeria became infected and died from the disease [1]. LASV, similar to other arenaviruses, is a negative-strand RNA virus whose enveloped virions are pleiomorphic in nature and range from 40 to 300 nm in diameter [2,3]. Arenavirus genomes consist of two ambisense single-stranded RNA segments referred to as the small (S) and large (L) segments. The 7.2 kb L segment encodes both the viral RNA-dependent RNA polymerase (RdRp) as well as the zinc-binding protein. The 3.4 kb S segment encodes the glycoprotein precursor complex (GPC) along with the nucleoprotein [4]. The GPC is co- and post-translationally cleaved into the signal peptide, GP1, and GP2. The natural reservoir of LASV is the peridomestic multimammate rodent, (Mastomys). Mastomys are distributed throughout sub-Saharan Africa with multiple identified phylogroups throughout their extensive range [5]. Recent studies have also implicated Nr2f1 the rodent species and as additional reservoirs of LASV, but their impact on overall disease burden is currently undetermined [6]. LASV spillover from Mastomys into humans is thought to occur via many routes, including direct contact with rodent excreta, inhalation of aerosols containing rodent excreta, through rodent bites, and through rodent handling and consumption [7,8]. Incidence rates of LASV have been correlated to seasonal changes, specifically rainfall, which is believed to correspond to alterations in the interaction between Mastomys and humans [9,10]. Direct human to human transmission, including cases of nosocomial transmission, have also been observed through exposure to the virus stemming from contact with the blood or other bodily fluids from infected individuals [7,10,11,12,13]. An approximate 300,000 to 500,000 LASV infections with an associated 5000 to 10,000 deaths, occur annually across sub-Saharan west Africa, with the vast majority of viral burden occurring in Nigeria, Sierra Leone, Liberia, and Guinea [9,14,15]. Consistent with these numbers, it is estimated that 80% of infections result in sub-clinical infection or mild illness, while 20% of infections result in more severe disease that require hospitalization [7]. The case fatality rate from severe/hospitalized cases reaches 15%, with the overall case fatality rate of LF being about 1% [7,12]. The incubation period for LF ranges from 6C21 days. Symptoms of LASV infection can be non-specific and LF is often only considered as a potential cause of illness after exclusion of other diseases such as typhoid fever and malaria. Early clinical symptoms include weakness, malaise, fever, sore throat, body pains, nausea, vomiting, diarrhea, and cough [7,9]. Late stage clinical manifestations include mucosal and internal bleeding, seizures, coma, disorientation, and deafness. Patients RG2833 (RGFP109) typically succumb to disease within 14 days of initial symptom onset [9]. Currently, off label use of ribavirin, fluid replacement, and dialysis are used for treatment of severe LF [16,17]. Since its initial identification in 1969 about 30 cases of exported LASV have been reported in 9 RG2833 (RGFP109) RG2833 (RGFP109) non-endemic countries. LASV therefore represents a serious exposure risk to healthcare workers and a significant public health concern worldwide [18]. Because of its epidemic potential and the current lack of approved vaccines or treatments, LASV was added to the WHO List of Blueprint Priority Diseases/Pathogens in 2018. Together, the substantial disease burden in endemic countries and continued threat from LASV exportation to non-endemic regions emphasizes the need for a maintained effort to develop countermeasures for LASV and to prepare for potential outbreaks. This review will discuss antivirals currently in use or under investigation for treatment of LASV infection, focusing on those therapeutics that have already been tested in preclinical animal models or humans. Abbreviations are summarized in Supplementary Table S1. 2. Preclinical Models Several animal models have been developed to investigate LASV disease and pathogenesis and have demonstrated differing utility for testing of therapeutic countermeasures against the virus. The pros and cons of these models, which include guinea pigs, mice, and non-human primates (NHPs), have recently been examined [19,20]. Inbred Strain 13 and outbred Hartley guinea pigs are considered the small animal models of choice.