Introduction and Background of the Project

Introduction

Malaria continues to be a major burden for the people in Tropical and subtropical regions, causing 619,000 deaths, mostly children under five, and 247 million cases in 2021¹. The artemisinin-based combination therapy (ACT) is the current first-line therapy, however, the rise and spread of drug- resistant parasites threaten this effective treatment. Therefore, the need for novel, safe, and effective drugs to overcome drug resistance is paramount for global health. Shionogi & Co., Ltd. and Nagasaki University have been working together to provide a novel treatment option for drug resistance in malaria since 2019². In this partnership, 80,000 compounds from Shionogi’s chemical library were screened with a novel phenotypic method established at Nagasaki University against the asexual blood stage of P. falciparum. With the support of Medicines for Malaria Venture (MMV), 5 structurally novel hit series with fast-acting properties were identified. In this project, Hit to Lead study for these hits will be conducted to identify a novel lead series that could overcome the drug resistance issue and provide single dose treatment.

Project objective

The objective of this project is to identify a novel lead series that could overcome the drug resistance issues and satisfy the MMV’s early lead criteria³ by conducting structure activity relationship (SAR) study for five novel hit series.

Project design

This project will be divided into two parts. In the first part, all 5 hit series will be explored to understand their potential for higher potency, safety and the activity on known drug resistance strains within 6 months. In the second part, one or two series will be prioritized, and we will continue the SAR study for further potency and characterization of the series. A promising series will be subjected to in vivo efficacy study in mice.

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

According to WHO, children under 5 accounted for about 80% of all malaria deaths in 20211. This project aims to provides a novel drug that is safe for high-risk populations, such as children under 5 and pregnant women, and effective on drug resistant parasites. By delivering a novel treatment option for patients, we would like to commit the global health toward the malaria control and elimination.

What sort of innovation are you bringing in your project?

The novel hit series in this project have novel chemical structures as antimalarials and are potentially working with novel mechanism of action, which is important to ensure the activity on drug resistant parasites. The hit series were also confirmed to have fast-acting properties, which is desired for a novel treatment drug. In this project, we aim to identify a novel lead series by utilizing novel pharmacological assays established at Nagasaki University in the SAR study.

Role and Responsibility of Each Partner

Shionogi leads the SAR study by designing and synthesizing novel compounds, and conducts pharmacokinetics and safety evaluations. Nagasaki University provides parasitological expertise and conducts studies to characterize the compounds. MMV supports the project by giving advice based on their expertise in antimalarial drug discovery and provides some essential assays to differentiate our series from the existing drugs.

Others (including references if necessary)

1. WHO fact sheets (8 December 2022)

https://www.who.int/news-room/fact-sheets/detail/malaria

2. Shionogi & Co., Ltd.　Press release　(28 February 2019)

https://www.shionogi.com/content/dam/shionogi/jp/news/pdf/2019/190228_012.pdf

3. MMV Frontrunner template: early leads

https://www.mmv.org/research-development/information-scientists