Advancements in Antimalarial Drug Discovery and Development

The recent webinar "Advancing Malaria Drug Discovery" convened leading researchers from Medicines for Malaria Venture (MMV), Gates Foundation, University of California San Diego, University of Cape Town - H3D, and Collaborative Drug Discovery to discuss current challenges and emerging solutions in antimalarial research.

Current Malaria Burden and Resistance Challenges

Despite decades of intervention efforts, malaria remains a significant global health challenge. World Health Organization data from 2023 indicate over 250 million cases annually, resulting in more than 600,000 deaths. The burden disproportionately affects Africa, with vulnerable populations including children under five and pregnant women bearing the greatest risk.

Drug resistance presents the primary obstacle to effective treatment. Resistance to artemisinin combination therapies (ACTs), particularly artemisinin and lumefantrine components of Coartem, continues to emerge. MMV has implemented a three-pronged strategy addressing this challenge: multiple first-line therapies with different partner drugs, advancement from dual to triple combinations, and incorporation of single low-dose primaquine to eliminate gametocytes before transmission.

Pipeline Developments and Big Bets

Next-Generation Therapeutics

MMV's pipeline includes several transformational approaches:

Long-Acting Chemoprevention: Development of once-monthly oral molecules with extended half-lives for vulnerable populations. The strategy includes exploration of long-acting injectables, following successful models from HIV pre-exposure prophylaxis, particularly lenacapavir's six-month protection profile.

Single-Dose Cure Combinations: Focus on elimination tools requiring only one administration, incorporating radical cure capabilities for P. vivax hypnozoites while maintaining low resistance risk.

Severe Malaria Treatment: MMV383 entering Phase I trials as potential replacement for injectable artesunate in resistance scenarios.

Transmission-Blocking Approaches: Investigation of endectocides for elimination campaigns, utilizing the human body as a drug carrier to kill mosquitoes during blood meals.

Beyond Small Molecules

The research community is expanding beyond traditional small molecule approaches. Current investigations include:

• Nanobodies and monoclonal antibodies
• Self-amplifying DNA/RNA expressing monoclonal antibodies
• Antisense oligonucleotides offering naturally long-acting properties
• Small protein scaffolds

These modalities aim to combine advantages of vaccines (safety in vulnerable populations) with small molecule benefits (affordability and efficacy).

Target Discovery and Structure-Guided Design

The transition from phenotypic screening to structure-guided drug design represents a significant advancement. The community has focused on discovering new targets through resistance evolution studies, though this approach inherently creates resistance risk.

Research on prolyl-tRNA synthetase exemplifies how detailed target understanding can mitigate resistance. Studies revealed that inhibitors targeting the proline binding site create resistance through unrelated transporter mechanisms, while ATP binding site inhibitors avoid this issue. This demonstrates the importance of binding mode specificity in resistance risk assessment.

Compilation of resistance mechanisms through the Malaria Drug Accelerator has revealed patterns in resistance-conferring mutations, enabling development of artificial intelligence approaches for resistance prediction in future compound design.

Artificial Intelligence and Open Science Initiatives

AI Applications

Multiple AI initiatives are accelerating discovery timelines:

• MMV Solar: Free access to dose prediction functionalities
• MMV Free: Interface for chemoprevention molecule property prediction
• DD4GH (Drug Design for Global Health): Collaboration with Deep Mirror providing free access to machine learning capabilities for global health scientists, launching March 2025

The AI workflow encompasses structure modeling, generative virtual compound design, property prediction, compound triage, and iterative model improvement through feedback loops.

Open Science Efforts

Since 2012, MMV has distributed compound libraries to over 50 countries through open access initiatives. Current programs include:

• Compound libraries shared openly with product development partnerships
• Collaborative drug discovery programs (Malaria Libre)
• In vivo testing setup (MVI)
• Mentorship programs supporting African natural product research

CDD's African program provides technology access grants to level the playing field for African scientists working on malaria and tropical diseases.

African Research Capacity and Community Engagement

Rationale for African R&D

Three key factors drive the importance of conducting research in Africa:

1. Disease Burden: 94% of malaria cases occur in Africa, necessitating local research capacity
2. Genetic Diversity: Direct links between population genetics, environment, and treatment response require proximate research
3. Metabolic Variability: African genetic diversity in drug-metabolizing enzymes remains poorly understood due to limited clinical trial representation (4% of global trials)

Pharmacogenomics Research

Project Africa Gradient utilized transfer learning from oncology to identify genetic variants prevalent in Africa affecting malaria and tuberculosis drug metabolism. This approach addresses the lack of African biobanks while enabling incorporation of genetic effects into physiologically-based pharmacokinetic models for tailored dosing recommendations.

Future Directions

Expert panel predictions for the next 5-10 years emphasize:

Polypharmacology: Development of single agents affecting parasites at multiple stages to address resistance

Super-Selective Inhibitors: Leveraging detailed target knowledge for compounds providing extended protection while mitigating resistance risk

Long-Acting Injectables: Following lenacapavir's precedent for six-month protection profiles

Biologics Integration: Particularly for safety in pregnant women and women of childbearing potential