Over 1.7 billion people throughout the world are affected by neglected tropical diseases (NTDs), most of whom are women, children, and individuals with disabilities residing in tropical and subtropical regions in the Americas, Southeast Asia, and Sub-Saharan Africa.1
NTDs can be transmitted by several different types of vectors, including flies, mosquitoes, parasitic worms, bacteria, and protozoa. Increasing awareness, actively seeking cases, and providing funding to support elimination efforts are crucial to tackling NTDs.
NTDs often affect people from low to middle-income countries, who typically cannot afford to buy drugs. As a result, there remains a lack of appropriate treatments for NTDs due to historically limited interest by pharmaceutical industries in funding research on these diseases. In fact, only 16 drugs were approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 1975 and 2011 for treating NTDs.
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Challenges in Drug Discovery for Emerging and Neglected Tropical Diseases
Several major challenges are associated with treating NTDs worldwide. Widespread antimicrobial resistance, for example, has made previously effective drugs unable to control the spread of NTDs, particularly among vulnerable populations. Reduced drug efficacy has also been observed in the treatment of leprosy, African trypanosomiasis, and leishmaniasis1.
The lack of pharmaceutical funding for NTDs has also led to a limited understanding of the basic biology associated with the organisms that cause these diseases. Likewise, the lack of screening platforms and translational programs has limited the success of drug discovery programs.
Compared to conventional target-based screens that have been involved in NTD drug discovery, phenotypic-based whole-organism screening assays offer several advantages.
Some of these advantages include the lack of validated targets available for NTDs, the innate complexities associated with the pathophysiology of these diseases, and the profound need to develop effective treatments in a timely manner.
World Neglected Tropical Diseases Day 2024
Strategies to Overcome Challenges
At country level, coordination among interventions targeting different NTDs, between the NTD program and other health programs, and between ministries of health and other sectors are crucial to translate global policies into locally integrated services and achieve the set targets and goals, towards control, elimination, and eradication of NTDs.”
World Health Organization.5
In January 2021, the World Health Organization published a ‘road map’ for NTDs, which sets global targets and milestones that must be met to eradicate all 20 NTDs. This new road map aims to bring Member States and other stakeholders, including donors, implementing partners, and disease experts, together to align their strategies and plans towards the prevention and treatment of NTDs.
In addition to continuing mass drug administration programs, which are supported by drug donations provided by 11 pharmaceutical companies worldwide, new and improved surveillance tools will also be developed to monitor drug efficacy and antimicrobial resistance5.
The 2030 WHO roadmap for NTDs also emphasizes the importance of developing more effective drugs to ultimately improve patient outcomes and overcome the possible emergence of drug resistance.
Advances in Drug Discovery for Emerging and Neglected Tropical Diseases
Recent advances in automated microscopy have replaced traditionally laborious procedures associated with imaging analyses. Recently, high-content imaging screens have been used to validate the efficacy of thousands of compounds against helminth diseases like Schistoma parasites1.
In addition to imaging screens, high-throughput screening (HTS) of test compounds has also been conducted for protozoan parasites, including Trypanosoma brucei, Trypansoma cruzi, and Leishmania species.
The automation of HTS, combined with the miniaturization of otherwise highly complex assays, facilitates large-scale phenotypic screens for millions of compounds to be completed in a matter of several days, thereby facilitating the rapid identification of hit compounds for downstream validation studies4.
Robotics-enabled automated HTS are crucial for hit-to-lead and lead optimization programs conducted within the pharmaceutical industry. Over the past several decades, several drug candidates have been identified through the lead optimization of phenotypic hits.
Some of these include imidazolopiperazine, spiroindolones, artemisinin, and cyclosporin for the treatment of malaria, as well as benzoxazole, amido benzimidazole, and triazolopyrimidines for the treatment of kinetoplastida4.
The Current Global State of Drug Discovery
Perspectives on the Future of Drug Discovery for Emerging and Neglected Tropical Diseases
Recent advances in artificial intelligence (AI) technologies, particularly machine learning (ML), have been used to support drug discovery processes by selecting the most appropriate screening assay for a given disease of interest. ML and chemoinformatics platforms also allow researchers to predict the biochemical characteristics of potential hit compounds.
Novartis has successfully applied the profile-quantitative structure-activity relationship (pQSAR) platform, a highly versatile, accurate, and automated ML approach, to support phenotypic and target-based parasitic drug discovery programs.
This pQSAR-driven screening effort led to a hit rate of 23.5% and the identification of highly potent compounds with desirable pharmacological properties for the potential treatment of Plasmodium falciparum infection.
Several other in silico methods have been incorporated into drug discovery programs, some of which include QSAR, molecular docking, molecular dynamics simulations, and pharmacokinetics profiling3.
Computational simulations have also provided crucial insights into ligand-protein binding interactions to support lead compound optimization efforts.
Conclusion
In conclusion, while neglected tropical diseases (NTDs) continue to affect over 1.7 billion people globally, significant advancements in drug discovery are offering renewed hope.
Despite challenges like antimicrobial resistance and limited pharmaceutical funding, innovative approaches such as phenotypic-based whole-organism screening, automation of high-throughput screening, and the integration of artificial intelligence are accelerating the identification of potential treatments.
The World Health Organization's 2030 roadmap emphasizes the importance of global collaboration, mass drug administration, and the development of more effective drugs to achieve the control, elimination, and eradication of NTDs. Through continued innovation and strategic efforts, there is a promising path forward in overcoming these diseases and improving the lives of millions in vulnerable populations.
References
- Hudu, S. A., Jimoh, A. O., Adeshina, K. A., et al. (2024). An insight into the Success, Challenges, and Future perspectives of eliminating Neglected tropical disease. Scientific African 24; e02165. doi:10.1016/j.sciaf.2024.e02165.
- Johnston, K. L., Ford, L., & Taylor, M. J. (2014). Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A.WOL Experience. SLAS Discovery 19(3); 335-343. doi:10.1177/108705711357113511270.
- Ibrahim, M. T., Ja’afaru, S. C., Uzairu, A., et al. (2024). Computational design of novel therapeutics targeting Schistosomiasis, a neglected tropical disease. Scientific African 25. doi:10.1016/j.sciaf.2024.e02326.
- Rao, S. P. S., Manjunatha, U. H., Mikolajjczak, S., et al. (2023). Drug discovery for parasitic diseases: powered by technology, enabled by pharmacology, informed by clinical science. Trends in Parasitology 39(4); 260-271. doi:10.1016/j.pt.2023.01.010.
- “Ending the neglect to attain the Sustainable Development Goals: A road map for neglected tropical diseases 2021-2030” [Online]. Available from: https://www.who.int/publications/i/item/9789240010352.
Further Reading