Using advances in disease modelling to develop a new generation of drugs against malaria transmission
The CSIR, in collaboration with several partner institutions, have screened vast libraries of synthetic compounds that might be used in a new generation of antimalarial drugs that will disrupt the life cycle of the malaria parasite, paving the way for the eradication of the disease. Compounds have been identified that meet the criteria and exhibit the ideal characteristics required for further development.
Nearly half the world’s population continues to be at risk of contracting malaria, with Plasmodium falciparum representing the most prevalent parasite species of the disease. Despite recent gains in reducing the disease’s morbidity and mortality, malaria’s global burden remains high with 200 million cases and 438 000 deaths reported in 2015 alone.
The cost to the African continent is a loss in gross domestic product which is estimated to exceed USD$12 billion per year, and this impact is compounded by an ever-increasing parasite resistance to virtually all the existing anti-malarials; this is mirrored by increasingly widespread mosquito resistance to insecticides, including those used for long-lasting insecticide-treated bed-nets. This burden has placed pressure on scientists to develop more effective interventions to reduce the disease’s health impact, and has led to renewed, accelerated efforts to eliminate and eventually eradicate the disease.
The Malaria Eradication Agenda represents the key global framework for defining innovative strategies to reduce the malaria burden and eventually achieve eradication. Central to this agenda lies the urgent need to develop a new generation of antimalarial drugs that have unique chemical properties; namely drugs that not only act to expeditiously clear parasite infection, but represent long-acting post-treatment prophylaxis, possess host/vector transmission-blocking ability, and result in a radical single exposure cure of the malaria species that affect humans.
For this to work, novel drugs are needed in parallel that provide single exposure chemoprotection. The need to identify such antimalarials, capable of inhibiting parasite growth at multiple stages of development, underscores the team’s current research efforts. In particular, researchers are focused on developing and deploying technologies that rapidly identify transmission-blocking compounds that prevent specific forms of malaria (gametocytes) from being transmitted from humans to the mosquito vector.
Significant challenges exist in finding such compounds, due amongst other factors to major shortfalls associated with accurately replicating, in vitro, the endogenous host environment and key gametocyte development stages associated with disease transmission; the unique metabolic homeostasis of malaria during these stages; and the significant bottlenecks associated with producing sufficient biomass representing the parasite during transmission. Despite these challenges, the CSIR team has successfully developed highly efficient gametocyte generation technology, and through collaboration with local and international research groups, has been exploiting this to deploy robust medium to high-throughput bioassays that permit rapid identification of transmission-blocking antimalarial compounds.
After an extensive process of technology validation, the team’s efforts are currently focused on rapidly screening large new compound library collections, in order to identify a novel diverse compendium of pharmacologically distinct compounds that possess potent transmission-blocking antimalarial activity. To date several thousand compounds have been interrogated, yielding a subset that meet the criteria and exhibit the ideal characteristics required for further development.
Together with collaborating partners these and other compounds identified in future will form the basis of drug development efforts aimed ultimately at creating drugs that combat and reduce malaria’s transmission. In the process, highly skilled local expertise in developing and implementing high-throughput compound screening infrastructure, undertaking industrial-scale screens, and knowledge and process management in high-throughput screening is being developed towards strengthening the country’s nascent drug discovery and development capacity.
This initiative is being performed in collaboration with the Universities of Pretoria, the Witwatersrand/NHLS, the Cape Town H3D Centre, and the Medicines for Malaria Venture through funding provided by the MRC Strategic Health Innovation Partnerships programme and the CSIR.
Dr Dalu Mancama