Introduction and Background of the Project

In the world malaria, caused by Plasmodium protozoa, is still one of the most life-threating infectious diseases and an estimated 585,000 people die every year, especially children in African countries. To treat malaria, the artemisinins, antimalarial drugs, are widely used as the first-line treatment. However, the recent studies have reported the emergence of resistant parasites.^{1, 2}. Artemisinin is an antimalarial drug identified through the work of Prof. Youyou Tu, for which she received the Nobel Prize for Medicine in 2015. Because no vaccines with sufficient prophylactic efficacy are yet available, chemotherapy is also the most effective tool for treatment and prevention of malaria. As a common standard for new antimalarials toward the eradication of malaria, Medicines for Malaria Venture (MMV) has defined through its research the Target Product Profiles (TPP) and associated Target Candidate Profiles (TCPs), which are characteristics of compounds to be found in such future antimalarials, as defined in the TPPs³. On the other hand, Eisai had started multiple antimalarial projects with its library compounds and collaborated with MMV, aiming to contribute to the eradication of malaria by bringing novel drugs to patients.

The aim of this project is the optimization of our hit compounds to obtain new lead compounds with a new mode-of-action (MOA). As a start point for chemical modification, we had obtained several antimalarial hit series with different characteristics and chemical structures. Eisai and MMV had screened 20,000 compounds of Eisai’s library in GHIT Fund’s Screening Platform program and identified several hit series which show antimalarial activities against malaria parasites at multiple life stages. Furthermore, in its original antimalarial project, Eisai has identified compounds, with a new MOA, which inhibit glycosylphosphatidylinositol (GPI) biosynthesis. In the GPI project, Eisai had also identified a hit series through an internal target-based screening and one of these hit compounds showed in vivo efficacy in animal models. Combining Eisai’s library compounds as well as knowledge of medicinal chemistry and drug discovery with MMV’s expertise in malaria research, the project strives to find novel lead compounds which will become the next generation antimalarial drugs.

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

In the world, malaria is still one of the most life-threating diseases with the majority of the victims being young children, especially in African countries. The global community is working together toward the common goal, the eradication of malaria. To control and eradicate infectious diseases, vector control, the use of vaccines to prevent infection and treatment with drug are equally important. For malaria, each of them is under evaluation. While antimalarial drugs have shown memorable improvements in last century, but the recent studies suggest the potential impact of new parasites with resistance against the existing therapy. The Eisai-MMV project has been proposed to contribute to the eradication of malaria by providing lead compounds with novel and unique MOA for novel drugs. Currently strategic target profiles are set for next generation of antimalarial drugs targeting eradication, and this project is planned to fulfill one or more of these target profiles. The final goal of antimalarial drugs to treat malaria, as defined in TPPs, is a Single Exposure Radical Cure and Prophylaxis agent (SERCaP). An ideal SERCaP drug will be constituted with four TCPs (TCP-1 as a fast killing drug, TCP-2 as a long-acting drug, TCP-3a as an anti-relapse agent and TCP-3b as a transmission blocking agent)³. All hit series delivered into this project shows not only antimalarial activity leading to TCP-1 or 2, but also additional preferable characters (identified or expected from scientific rationale). Also, most of these hit series has novel chemical pharmacophores and this will lower the risk of cross-resistance with existing antimalarial drugs, such as the artemesinins. Bringing lead compounds with novel MOA and potent activities against parasites at multiple life stages　is highly expected to lead the new antimalarial drugs development to help save the lives of many children in endemic areas.

What sort of innovation are you bringing in your project?

It is to be mentioned that lead compounds expected in this project have novel MOA and activities against parasites at multiple life-stages. To achieve these objectives, multiple hit series were brought to this project from two approaches, GHIT Screening Platform and GPI-biosynthesis inhibitor. Regarding MOA, most of the hit series that will be investigated by Eisai and MMV have shown to have a chemotype different from current available or known antimalarials, and one of the hit series is shown to have a new MOA that inhibits GPI biosynthesis. Furthermore, hit compounds will first be screened to see if their MOA is the same as existing antimalarial drugs, allowing us to prioritize novel MOAs. Multi-stage activities mean to act on parasites in different life stages. In the previous Screening Platform, hit series which showed antimalarial activities in two or more life stages of parasites were selected and brought to this project. Inhibition of GPI-biosynthesis is also expected to lead to antimalarial activities against multiple parasite life stages, because many kinds of stage-specific GPI-anchored proteins are expressed in each life stage of the malaria parasite. In addition to drug resistance, another major problem is that there are few transmission-blocking drugs and anti-relapse drugs among currently available therapeutics, except for primaquine. Selected new hit series would have the potential to block the transmission of parasites from hosts to mosquitos and the relapse of vivax malaria in liver. Based on these discussions, such a new antimalarial would show no cross-resistance to existing antimalarial drugs and provide a new option for malaria treatment by targeting multiple life stages of malaria parasites.

The additional advantage of targeting GPI biosynthesis is a novel MOA with an identified target protein. The target protein named as Gwt1p, an acyltransferase essential in GPI-biosynthesis, was discovered in Eisai^4-7. This MOA was also evaluated for other pathogenic microorganisms and a candidate compound for clinical trials was identified in the previous antifungal project of Eisai^8-10.

Role and Responsibility of Each Partner

Eisai proceeds with the project in collaboration with MMV to provide the world with new drug candidates for the treatment of malaria. Leveraging its strength in medicinal chemistry, Eisai synthesizes novel anti-malarial candidate compounds, and then conducts primary anti-malarial assays, physicochemical assays, DMPK assays, and primary safety studies so that Eisai can identify lead compounds.

MMV works in partnership with Eisai, providing drug discovery expertise and strategic input to the project.  MMV also has the responsibility to connect the team with partners in the MMV network so that malaria screening data on selected project compounds is available to aid decision making.

Others (including references if necessary)

References

1. Yeung S, Socheat D, Moorthy VS et al. Artemisinin resistance on the Thai-Cambodian border. Lancet 2009; 374: 1418-9.

2. Hawkes M, Conroy AL, Kain KC. Spread of artemisinin resistance in malaria. The New England journal of medicine 2014; 371: 1944-5.

3. Burrows JN, van Huijsduijnen RH, Mohrle JJ et al. Designing the next generation of medicines for malaria control and eradication. Malaria journal 2013; 12: 187.

4. Okamoto M, Yoko-o T, Umemura M et al. Glycosylphosphatidylinositol-anchored proteins are required for the transport of detergent-resistant microdomain-associated membrane proteins Tat2p and Fur4p. The Journal of biological chemistry 2006; 281: 4013-23.

5. Sagane K, Umemura M, Ogawa-Mitsuhashi K et al. Analysis of membrane topology and identification of essential residues for the yeast endoplasmic reticulum inositol acyltransferase Gwt1p. The Journal of biological chemistry 2011; 286: 14649-58.

6. Tsukahara K, Hata K, Nakamoto K et al. Medicinal genetics approach towards identifying the molecular target of a novel inhibitor of fungal cell wall assembly. Mol Microbiol 2003; 48: 1029-42.

7. Umemura M, Okamoto M, Nakayama K et al. GWT1 gene is required for inositol acylation of glycosylphosphatidylinositol anchors in yeast. The Journal of biological chemistry 2003; 278: 23639-47.

8. Miyazaki M, Horii T, Hata K et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrobial agents and chemotherapy 2011; 55: 4652-8.

9. Hata K, Horii T, Miyazaki M et al. Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis. Antimicrobial agents and chemotherapy 2011; 55: 4543-51.

10. Watanabe NA, Miyazaki M, Horii T et al. E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis. Antimicrobial agents and chemotherapy 2012; 56: 960-71.