Introduction and Background of the Project

1.Introduction

The order Bunyavirales comprises various families of negative-sense single-stranded RNA viruses. They can infect plants, livestock, and humans, posing significant challenges to health and economic stability. Among these families, notable ones include Arenaviridae, Nairoviridae, Hantaviridae, and Phenuiviridae, which are home to prominent human pathogens like Lassa virus, Hantaan virus, Crimean-Congo hemorrhagic fever virus, and Rift Valley fever virus (RVFV). RVFV infection can lead to severe hemorrhagic fever, with a mortality rate of nearly 70% in young animals. Importantly, RVFV can also infect humans through mosquito bites, causing conditions such as encephalitis, retinopathy, or disseminated intravascular coagulation, leading to hemorrhage and, in severe cases, mortality rates of around 20%.

Currently, a live-attenuated vaccine candidate called MP-12 exists and has shown promising initial results in clinical trials with mild side effects. However, no vaccine or other therapeutics have been licensed against RVFV.

2.Project objective

The project aims to use a live virus platform to identify potential compounds active against the Rift Valley fever virus (RVFV) using the RIKEN NPDepo library. Furthermore, the project intends to investigate the activity of selected compounds against the Punta Toro virus and La Crosse virus in order to identify potential broad-spectrum anti-bunyavirus compounds. This collaboration leverages the screening capabilities and drug development expertise of Japan’s largest comprehensive research institution, PDP, and academic investigators to achieve its goals.

3.Project design

The initial screening will involve using the MP-12 strain of RVFV to infect human hepatocyte cells. A subset of the RIKEN NPDepo library (20,000 compounds) will be screened in a 384-well plate with a single compound concentration of 10 µM. The results will be evaluated for antiviral activity and cell viability, and potential hits will be chosen based on specific criteria.

About 100 compounds (assuming a 0.5% hit rate) will be selected from the screening for further confirmation studies. These studies will involve testing the compounds at three different doses in cultured cells infected with RVFV, similar to the initial screen, and assessing cytotoxicity. From the confirmed compounds, RIKEN and MMV will prioritize up to 5 hits for further evaluation.

To assess the potential for broad-spectrum anti-bunyaviral activity, the confirmed compounds will be tested against Punta Toro virus and the more distantly related La Crosse virus.

The hit series meeting MMV and GHIT criteria for further development (hits with confirmed EC50 < 5 µM against live viruses and a selectivity index (SI = CC50/EC50) of ≥10, with progressable chemotypes) will form the basis of a future GHIT HTLP. 

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

RVFV is a featured list of pathogens that require urgent attention in pandemic preparedness. Currently, no therapeutics are available for these viruses, which poses an enormous challenge to global health security due to high mortality rates and lack of therapeutic options. The absence of effective medical interventions, combined with challenges in implementing robust public health measures in affected areas, highlights the urgent need for safe and effective vaccines, antiviral therapies, and comprehensive strategies to mitigate the impact of RVFV on human and animal health. To address this threat, MMV and RIKEN are collaborating to discover potential broad-spectrum anti-bunyaviruses compounds.

What sort of innovation are you bringing in your project?

There is an unmet need for drugs active against bunyaviruses and Rift Valley 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 bunyaviruses.

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 the University of Pennsylvania, Cherry's Lab, which has extensive experience working with the Bunyavirales family. 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.