Introduction and Background of the Project

1.Introduction

The Filoviridae family comprises elongated filamentous viruses with genomes composed of negative-strand single-stranded RNA. Typically harbored in reservoir species like bats, these are zoonotic viruses, opportunistically crossing over to infect humans and other mammals, leading to severe and often fatal haemorrhagic fever. Among its most notorious members are the Ebola virus (EBOV), Marburg virus (MARV), and Sudan Ebola virus (SUDV), all associated with recent outbreaks in Africa. The EBOV outbreak spanning from 2014 to 2016 in West Africa stands as the most severe on record, with over 28,000 suspected cases and more than 11,000 fatalities ¹. MARV has also caused sporadic outbreaks in Uganda, the Republic of Congo, Guinea, Ghana, and other African nations, with mortality rates ranging from 24 to 88% ².

2.Project objective

The project aims to use a multi-filovirus "rainbow" system that can simultaneously test for EBOV, MARV, and SUDV using a single cell line to identify potential treatments against filoviruses using the RIKEN NPDepo library. Additionally, the project seeks to study the effectiveness of selected confirmed hits against other filoviruses (Tai Forest, Reston, Bundibogyo, Lloviu) 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 be performed on a subset of the RIKEN NPDepo library (20,000 compounds). 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 against live Ebola virus. Selected hits meeting specific criteria will be considered for future development.

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

Currently a vaccine against Ebola has been approved by FDA, but information about the duration of protection, vaccine effectiveness in outbreak situations, and the need for booster doses are still lacking³. Prophylactic measures are limited to isolating infected individuals, and patient care focuses primarily on managing symptoms, as there's no specific treatment available. The urgency for pandemic preparedness is underscored by the high mortality rates associated with filoviruses and the lack of therapeutic options. To address this threat, MMV and RIKEN aim to identify potential broad-spectrum anti-filovirus 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 filoviruses, Ebola and Marburg 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 filoviruses.

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 KU Leuven in the Maes’ lab, who has extended experience working with filoviruses. The studies will be conducted in collaboration between RIKEN, MMV, and MMV partner test centers.

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

Others (including references if necessary)

1. Malvy D., (2019). Ebola virus disease. The Lancet 393, 936–948.

2. Hampton L.M. (2023). Ebola outbreak detection and response since 2013. Lancet Microbe 4, e661–e662

3. Kieh M, et al. (2022). Randomized Trial of Vaccines for Zaire Ebola Virus Disease. N Engl J Med. 29;387(26):2411-2424.