Introduction and Background of the Project

Introduction

Alphaviruses, belonging to the Togaviridae family, are small, enveloped RNA viruses with a single-stranded, positive-sense RNA genome. They are typically transmitted by arthropods and are known to cause diseases in both humans and animals¹. New World alphaviruses, such as Venezuelan and Western equine encephalitis viruses (VEEV and WEEV), are commonly associated with encephalitic diseases¹. Conversely, Old World alphaviruses like Chikungunya virus (CHIKV) and Mayaro virus (MAYV) generally cause arthritogenic febrile illness¹. Acute chikungunya manifests with high fever, arthralgia, headache, and nausea. Approximately 51% of symptomatic individuals experience chronic sequelae, including persistent arthralgia, myalgia, chronic arthritic disability, and increased mortality associated with the disease².

Project objective

The project aims to use advanced computer-assisted screening to find new compounds that can prove effective in combatting CHIKV. Initially, using state-of-the-art machine learning models, a large library of Eisai compounds will be screened in silico. Thereafter, hits from the in silico screen will be tested in vitro using established assays. This collaboration brings together the power of artificial intelligence, antiviral screening, and drug development expertise from a pharmaceutical company, Product Development Partner (PDP), and academic investigators in a country where CHIKV is endemic.

Project design

The primary screening process will use an innovative two-step approach to maximize the available space for testing potential activity against CHIKV. Around 50 primary hits will be chosen for further activity confirmation studies. Eisai will provide additional compounds for conducting these assays. For selected compounds, dose response curves (EC50) will be generated in the CHIKV assay, and their cytotoxicity profile (CC50) will be evaluated using the MTS assay.

5-10 confirmed active compounds will be prioritized for further profiling. To further assess their potential for broad spectrum activity within a virus family, these confirmed active compounds will be profiled against other alphaviruses. To assess specificity for the alphavirus genus, these confirmed actives will also be tested against SARS-CoV2 and mosquito-borne flaviviruses.

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

Currently, there are no approved treatments for CHIKV infection. Patient treatment primarily involves supportive care, typically prescribing non-steroidal anti-inflammatory drugs to alleviate symptoms. Vaccines against CHIKV have recently been approved, however, there is limited knowledge about the duration of their protection and their efficacy in preventing outbreaks. To address this challenge, MMV and Eisai aim to identify novel compounds against CHIKV using AI-enhanced screening of Eisai’s compound library. This effort could potentially lead to the development of new therapeutics for CHIKV and related alphaviruses.

What sort of innovation are you bringing in your project?

There is an unmet need for drugs active against alphaviruses and Chikungunya in particular. Our project aims at identifying new starting points for drug discovery against viruses for which there are currently no drug candidates. The Eisai library of small molecules has never been screened against alphaviruses. AI-based approach will enable selection of the most promising 9,000 compounds out of a large collection of >200,000 compounds.

Role and Responsibility of Each Partner

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

The project will be carried out by a team consisting of scientists and project managers from Eisai and MMV. Eisai will provide a library of over 200,000 compounds that have not yet been tested against the target virus of this proposal. The AI-based screening of the Eisai library will be performed using a phenotypic machine learning model developed by Prof. Alan Talevi’s team at the Universidad Nacional de La Plata (UNLP), Argentina. From this computational screen, the top 9,000 compounds will be selected and provided by Eisai for primary experimental screening by Prof. Diego Alvarez’s team at Universidad Nacional de San Martín (UNSaM), Argentina. The studies will be conducted in collaboration between Eisai, MMV, and Eisai's 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. Levi, L. I. & Vignuzzi, M. Arthritogenic Alphaviruses: A Worldwide Emerging Threat? Microorganisms 7, (2019).

2. Kang, H. et al. Chikungunya seroprevalence, force of infection, and prevalence of chronic disability after infection in endemic and epidemic settings: a systematic review, meta-analysis, and modelling study. Lancet Infect Dis 24, 488–503 (2024).