Malaria, which is caused by several protozoan Plasmodium species that transmit the disease through mosquitoes, continues to affect individuals throughout the world, particularly in sub-Saharan Africa, where 95% and 96% of cases and deaths occur, respectively1.
Common symptoms associated with malaria can include fever, headache, malaise, weakness, gastrointestinal distress, dizziness, confusion, disorientation, and, in severe cases, coma.
Image Credit: Jarun Ontakrai/Shutterstock.com
Introduction
Despite the World Health Organization's (WHO) Global Technical Strategy (GTS) goal to eradicate malaria by 2030, case numbers have increased over the past several years. In 2021 alone, over 247 million malaria cases were reported, 619,000 of which resulted in death, a significant rise of 33 million cases and 181,000 deaths compared to those reported in 2015.
Several antimalarial drugs are currently available to limit the detrimental effects of this disease and reduce associated mortality. However, many of these drugs are associated with limitations that prevent their widespread availability. Resistance to malaria medications also necessitates continuous monitoring and the identification of new candidate drugs with superior efficacy profiles.
Advances in Anti-Malarial Drug Discovery
Current malaria therapies
Suspected malaria cases must be quickly identified and treated to reduce the risk of mortality, as this disease can evolve rapidly into lethal symptoms. Some of the most widely used treatments for uncomplicated Plasmodium falciparum malaria include artemisinin (ART)-based combination treatments (ACTs), which include aremether-lumefantrine (AL) and artesunate-amodiaquine, which comprise 75% and 24% of the African market share, respectively1.
Other less frequently utilized treatment options include combinations of dihydroartemisinin-piperaquine (DHA-PPQ), atovaquone-proguanil (Malarone), and quinine with doxycycline or clindamycin. The choice of treatment will depend on the patient’s age, severity of symptoms, and immune status.
Despite the availability of these treatments, there remains an urgent need to treat asymptomatic patients, as these individuals are still capable of spreading disease through dormant Plasmodium vivax parasites.
Furthermore, patients with severe malaria often cannot be treated with oral medications and, as a result, require injectable treatments like artesunate or quinine.
Novel small molecules
To date, many different drug candidates are being investigated in preclinical exploratory phases, as well as human volunteer and malaria patient exploratory phases. For example, several novel small molecules have been evaluated in patients with malaria, including ZY-19489 and ferroquine. Recent studies on the combination treatment of ZY-19489 and ferroquine indicate that single-dose and long-term efficacy may be possible in children1.
Other notable small molecules that have been identified and studied in humans include cabamiquine, cipargamin, and ganaplacide. The latter is considered the most advanced antimalarial, as it is highly potent and has a favorable pharmacokinetic and safety profile.
The combination of ganaplacide with lumefantrine, a partner drug traditionally used in ACTs, has been shown to reduce the risk of resistance while also maintaining efficacy in large patient cohorts1.
Monoclonal antibodies
The United States National Institutes of Health (NIH) is currently investigating the prophylactic efficacy of two monoclonal antibodies, CIS43LS and L9LS. CIS43LS targets the circumsporozoite protein (CSP), which is crucial for parasites' ability to invade and infect hepatocytes.
Both phase I and phase II clinical trials have demonstrated that CIS43LS is associated with over 88% efficacy for at least six months1. As compared to CIS43, the parent antibody of CIS43LS, L9LS, has been shown to be three times more potent.
MMA01 and TB-21F are other monoclonal antibodies being investigated for malaria prophylaxis. Despite their potential, monoclonal antibodies are expensive to produce and often require specific storage conditions; therefore, their practical use in low—and medium-income countries will be a challenge.
Targeting mosquitos
For several decades, insecticidal nets have been successful in mitigating malaria transmission; however, this approach has been shown to increase the risk of mosquito resistance.
As an alternative vector control method, researchers have investigated the potential of treating mosquitos with antimalarials to support malaria control and elimination.
Some of the different methods that have been investigated include genetically modifying mosquitos so that they are resistant to parasitic infection and systemic treatment of mosquitos with insecticides like ivermectin, lota liner, or isooxazoline1.
What Role do Natural Products Play in Modern Drug Discovery?
Challenges in Anti-Malarial Drug Discovery
Non-compliance with the three-day regimen for ART, as well as its short half-life, has contributed to resistance to this drug and, as a result, its limited efficacy in treating malaria. Both total and partial resistance to other malaria drugs have also been reported throughout the world.
‘’The development of plasmodium parasites resistance to many drugs shows that more innovative research is still required, particularly on discovery of small molecules with novel mechanisms of action and targeted delivery approach of drugs to specific organs/tissues in order to increase efficacy and reduce adverse drug interactions.3”
Malaria primarily affects sub-Saharan African populations, particularly those residing in the poorest areas of this region. Agencies like the Global Fund have historically provided these communities with free anti-malaria medications; however, limited funding has been available to support the production and subsequent distribution of these medications on a larger scale.
Furthermore, many pharmaceutical companies have excluded malaria and other tropical diseases from their portfolio due to the high cost of drug development and limited commercial return.
Strategies to Overcome Challenges
Despite the lack of innovative drug discovery by pharmaceutical companies, several programs have been developed to support the discovery and delivery of new antimalarials to high-risk populations.
The Medicines for Malaria Venture (MMV), for example, is funded by governments and philanthropic organizations worldwide to ensure the dissemination of current anti-malarial medications while also supporting research endeavors for next-generation treatments1.
The Malaria Drug Accelerator (MaIDA), formed in 2012, primarily focuses on discovering novel malaria targets and advancing phenotypic drug screening to ultimately identify highly efficacious drug candidates2. To date, MaIDA has facilitated the discovery and prioritization of several malaria targets and tool compound characteristics capable of their inhibition.
The Biggest Challenges in Drug Discovery
Future Directions in Anti-Malarial Drug Discovery
Recent advancements in artificial intelligence (AI) indicate that this technology is capable of leveraging existing data to identify hit compounds more efficiently and rapidly than traditional screening platforms.
DeepMalaria, a deep-learning program, has recently been trained on 13,446 antiplasmodial hit compounds from the GlaxoSmithKline (FSK) database that are currently being investigated for their anti-malaria potential.
In a 2023 study, DeepMalaria successfully identified 72.32% of active molecules with increasing accuracy in its ability to distinguish more potent compounds4. Although these results are promising, additional research is needed to determine the potential role of AI-based approaches in malaria drug discovery projects.
Multiomics technologies have been widely used over the past several years to understand better the biological mechanisms involved in Plasmodium falciparum infection. For example, genomics studies have provided important insights into the various stages of liver-stage infection with this parasite, which has been crucial for the identification of potential target genes involved in the development of severe malaria5.
Thus, future studies will continue to utilize omics-based methodologies to identify novel malaria targets and those involved in other protozoan diseases.
References
- Siqueira-Neto, J. L., Wicht, K. J., Chibale, K., et al. (2023). Antimalarial drug discovery: progress and approaches. Nature Reviews Drug Discovery 22; 807-826. doi:10.1038/s41573-023-00772-9.
- Yang, T., Ottilie, S., Istvan, E. S., et al. (2021). MaIDA, Accelerating Malaria Drug Discovery. Trends in Parasitology37(6). doi:10.1016/j.pt.2021.01.009.
- Umumararungu, T., Nkuranga, J. B., Habarurema, G., et al. (2023). Recent developments in antimalarial drug discovery. Bioorganic & Medicinal Chemistry 88-89. doi:10.1016/j.bmc.2023.117339.
- Arshadi, A. K., Salem, M., Collins, J., et al. (2019). DeepMalaria: Artificial Intelligence Driven Discovery of Potent Antiplasmodials. Frontiers in Pharmacology 10; 1536. doi:10.3389/fphar.2019.01526.
- Pandey, S. K., Anand, U., Siddiqui, W. A., & Tripathi, R. (2023). Drug Development Strategies for Malaria: With the Hope for New Antimalarial Drug Discovery – An Update. Advances in Medicine. doi:10.1155/2023/5060665.
Further Reading
The Role of Chemical Proteomics in Understanding Small Molecule-Protein Interactions