Introduction and Background of the Project

1.Introduction

Dengue fever and Zika fever are flavivirus infections prevalent in sub-Saharan Africa, South America, and Southeast Asia. Like malaria, these diseases are transmitted by mosquitoes. Climate changes, including warmer temperatures and changes in rainfall patterns, are increasing the geographical spread and scale of outbreaks of these mosquito-borne diseases. It is predicted that approximately 3.9 billion people worldwide will be at risk of infection in the future. Dengue fever has already spread to a scale that cannot be ignored in terms of public health, and the risk of pandemics for other infectious diseases such as Zika fever and West Nile fever is also increasing. This situation threatens sustainable human health and welfare. Currently, there are no effective drugs for these flavivirus infections. Therefore, there is a strong need for enhanced medical tools to control the spread of infections and suppress severe cases. To meet this medical need, Eisai Co., Ltd. (Eisai) and DNDi are working on developing new drugs for the treatment of flavivirus infections using the Eisai compound library.

2.Project objective

We aim to identify hit compounds that will serve as the starting point for new drug development by exploring novel compounds that exhibit antiviral activity against flaviviruses such as dengue virus and Zika virus.

3.Project design

To explore compounds that exhibit antiviral activity against dengue virus and Zika virus, we will screen two types of compound libraries, a focused library and a diversity library, using an image-based phenotypic assay system. In the phenotypic assay system, viral proteins and host cell nuclei are stained, and the antiviral activity of the compounds is determined by analyzing fluorescent confocal images. The focused library consists of compounds selected by a machine learning model developed using assay data accumulated by Eisai. By complementarily utilizing the diversity library, we efficiently explore compounds that exhibit antiviral activity. Ultimately, we aim to identify hit compounds that show activity against dengue virus and Zika virus to establish preliminary structure-activity relationships, physicochemical properties, and other relevant biological information.

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

The flavivirus genus includes many pathogens that cause significant public health issues, such as dengue fever and Zika fever. These viruses infect not only humans but also other mammals, making eradication extremely difficult. Furthermore, since these infections are primarily transmitted by mosquitoes, global warming increases the likelihood of their spread in both developing and developed countries. The social disruption caused by the SARS-CoV-2 (Coronavirus) pandemic is still fresh in our memory. To prevent a recurrence of such pandemics, the development of medical treatments, including therapeutic drugs, is a global health challenge. Through this project, we aim to contribute to sustainable human health and welfare by providing the world with antiviral drugs for flavivirus infections as a new medical tool.

What sort of innovation are you bringing in your project?

The innovation of our approach is the robustness and uniqueness of the phenotypic assay system and compound library used for screening. The phenotypic assay system allows for high-throughput and reproducible evaluation of antiviral activity directly on live viruses by quantifying the ratio of infected cells to total cells through imaging analysis. Additionally, the compound library is enriched with compounds that inhibit viral replication, selected by the machine learning model developed using Eisai’s accumulated assay data. This library also includes compounds filtered based on chemical issues and physicochemical profiles, making it suitable for the exploration of active compounds. Furthermore, the ability to rapidly obtain information on structure-activity relationships for active compounds is one of our strengths. By effectively combining these strengths, we aim to identify promising drug seeds.

Role and Responsibility of Each Partner

In this project, Eisai will lead the overall research as the representative institute, provide compound libraries, resupply active compounds, and generate structure-activity relationships as well as physicochemical information. DNDi will closely collaborate with the Institute Pasteur Korea, who will screen the library, and manage the progress of the screening. Both parties will be responsible for analyzing the data obtained from the screening, selecting active compounds, and determining their priority.