Introduction and Background of the Project

1.Introduction

Mammarenaviruses are responsible for chronic infections in rodents worldwide, being those the primary vector of transmission to humans ^1-2. Human infections typically occur through mucosal exposure to aerosols or by direct contact with infectious materials via abraded skin^1-2. The mammarenavirus Lassa (LASV) is highly prevalent in West Africa, infecting several hundred thousand individuals annually and leading to numerous cases of Lassa fever (LF). Each year, almost 300,000 cases associated with LASV are reported, causing over 5,000 deaths³. The onset of severe LF disease typically manifests as respiratory distress, facial swelling, and hemorrhage, while less common symptoms include shock, coma, and seizures, with 15-20% of hospitalized patients succumbing within two weeks of symptom onset^4.

2.Project objective

The project aims to use a cell-based, infection-free platform to identify potential treatments against LASV using the RIKEN NPDepo library. Additionally, the project seeks to study the effectiveness of selected confirmed treatments against lymphocytic choriomeningitis virus (LCMV), Tacaribe virus (TCRV), and Junin virus (JUNV) in order to identify potential broad-spectrum antiviral compounds. This collaboration leverages the screening capabilities and drug development expertise of Japan’s largest comprehensive institution, PDP, and academic investigators to achieve its goals.

3.Project design

The primary screen will use LASV-vRNP/293mRFP to assess a subset of the RIKEN NPDepo library. The screen will be in a 384-well plate format with a single compound concentration of 10 µM. Compounds will be evaluated for their antiviral activity and impact on cell viability. Approximately 200 compounds will be selected for further confirmation studies based on specific criteria. Confirmed actives will undergo broad-spectrum antiviral testing and prioritization for further profiling. Selected hits meeting specific criteria will be considered for future development.

How can your partnership (project) address global health challenges?

LASV is a list of pathogens that require urgent attention in pandemic preparedness. Currently, there are no FDA-licensed vaccines or drugs available to treat or prevent the infection. The only existing treatment for LASV is the off-label use of ribavirin, which is only partially effective and can cause significant side effects. To address this threat, MMV and RIKEN aim to identify potential broad-spectrum anti-mammarenavirus compounds, which can potentially lead to the future development of effective medical interventions for this disease, contributing to global health security and preparedness for future outbreaks.

What sort of innovation are you bringing in your project?

There is an unmet need for drugs active against mammarenaviruses and Lassa Fever in particular. Our project aims at identifying new starting points for drug discovery against for which there are currently no drug candidates. The RIKEN NPDepo library is a depository of small molecules  (druglike compounds, pure natural products and derivatives) and has never been screened against mammarenaviruses.

Role and Responsibility of Each Partner

As the designated grantee for this project, the MMV is responsible for delivering the work plan within the agreed timeline and budget and for GHIT reporting.

The project will be carried out by a team consisting of scientists and project managers from RIKEN and MMV. RIKEN will provide a library of 20,000 compounds that have not yet been tested against the target virus of this proposal. The library will be tested at Scripps in the de la Torre’s lab, who has extended experience working with mammarenaviruses. The studies will be conducted in collaboration between RIKEN, MMV, and MMV partner test centres.

All project data will be registered in a shared database managed by MMV and accessible to both partners.

Others (including references if necessary)

1. Fang J, et al. (2022). Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host-directed antivirals. Proc Natl Acad Sci USA. 119(30), e2201208119.

2. Sakabe S, et al. (2023). Molecular Engineering of a Mammarenavirus with Unbreachable Attenuation. J Virol. 31, 97(1): e0138522.

3. Hallam, H. J. et al. (2018). Baseline mapping of Lassa fever virology, epidemiology and vaccine research and development. NPJ Vaccines 3, 11.

4. Ronk, A.J., Lloyd, N.M., Zhang, M. et al. (2023). A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection. Nat Commun 14, 5603.

5. Kato N, et al. (2012). Construction of a microbial natural product library for chemical biology studies. Curr Opin Chem Biol. 16(1-2), 101-108.

6. Piotrowski, J.S. et al. (2017). Functional annotation of chemical libraries across diverse biological processes. Nat Chem Biol. 13, 982-993.