Introduction and Background of the Project

1.  Introduction

MMV’s current portfolio includes promising drug candidates with the potential to be part of single-dose combinations for malaria, though most focus historically has been on treatment rather than prevention. Effective treatment is essential for saving lives and controlling malaria, but ultimately eradicating the disease requires preventive measures. Developing chemoprevention agents is a beneficial strategy as they are cost-effective and can significantly reduce infection rates, interrupt the transmission cycle, and help eliminate malaria in specific regions. Chemoprevention can also clear asymptomatic infections, reducing overall morbidity and aiding eradication efforts. In malaria-endemic areas, seasonal malaria chemoprevention using sulfadoxine, pyrimethamine, and amodiaquine has effectively reduced mortality with a monthly regime. However, there is a preference for long-acting injectable agents that offer at least three months of protection. Our hit series demonstrates robust anti-malarial activity, excellent selectivity, low solubility, desirable pharmacokinetic properties, and can be synthesized cost-effectively. Initial studies also indicate that the hit series has a low likelihood of resistance and a novel mode of action. Given these attributes, we aim to advance this series as a lead candidate for long acting injectable (LAI) chemoprevention.

2,  Project objective

The project aims to optimize the hit series, prioritize the best candidates, and deliver an early lead for intra-muscular chemoprevention that meets MMV’s LAI Early Lead Criteria. The investigation will focus on the medicinal chemistry potential of the unique natural-product-inspired hit series as novel anti-malarial agents, ensuring synthetic tractability, cost-effectiveness, and the potential for optimizing long-acting injectable relevant anti-malarial properties. Additionally, the project will explore and characterize the novel mechanism of action with a low propensity to induce resistance.

3.  Project design

We will study the structure-activity relationship to define the essential features of the minimal three-dimensional pharmacophore structures, aiming to simplify their design. Scaffold diversification will be explored to enhance our compound library, with an emphasis on improving the properties of long-acting injectable compounds by maintaining low solubility, increasing metabolic stability, and achieving a balanced blend of potency, stability, and solubility. We will continue evaluating promising candidates based on established safety and effectiveness criteria and predicting their behavior in humans. This process includes assessing candidates for pharmacokinetics/dynamics, potential off-target activities, and injection site reactions using animal models.

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

Developing novel, long acting injectable anti-malarial chemoprevention drugs is crucial for advancing malaria prevention and elimination strategies. Unlike oral medications for treatment, injectables ensure consistent delivery and adherence, which is particularly beneficial in regions with limited healthcare access or high malaria transmission rates. These drugs can provide extended protection, reducing the frequency of administration and enhancing patient compliance. Moreover, their sustained efficacy helps mitigate the development of drug resistance, a critical concern in malaria control efforts. We seek to expand the arsenal of preventative options to meet the diverse needs of vulnerable populations like children and pregnant women, improving global efforts to combat malaria effectively.

What sort of innovation are you bringing in your project?

Our project has many innovative features, but its chemistry stands out the most. Inspired by natural products, our hit series can be synthesized efficiently in an enantiomerically pure form using streamlined, cost-effective, and highly stereo-controlled synthetic methods involving fewer than five steps, starting with inexpensive materials.

Role and Responsibility of Each Partner

Nagasaki University will handle overall project management and coordination, as well as provide parasitological expertise to evaluate newly synthesized compounds. The University of Tokyo will leverage its designing and synthesizing of these compounds. Shionogi will supervise the project from the medicinal chemistry point of view. MMV will oversee chemistry and biology operations and mentor the entire project. All team members will contribute collaboratively to the project strategy, experimental design, and data analysis, drawing on their experience developing novel antimalarials.