Awards

Fidele Ntie-Kang of the University of Buea in Cameroon will create a set of 400 natural products of African origin for screening against a range of diseases, including TB, neglected tropical diseases, viral diseases, and malaria. The set will consist of pure compounds derived from diverse African samples, encompassing plants, fungi, and bacteria, as well as marine sources. The team will work with collaborators to collect samples from Cameroon and across the African continent. The collection will be designed to be easily and inexpensively sourced, and it will include samples of African medicinal plants with known promise. They will prepare extracts and test purified compounds in a panel of assays for relevant diseases. For compounds showing activity in these assays, they will perform computational analysis of the chemical structure to explore the potential of related compounds.

Erick Strauss of Stellenbosch University in South Africa will develop small molecule anti-TB drugs that work by targeting bacterial proteins for degradation rather than inhibiting their activity. This strategy involves creating proteolysis targeting chimeras (PROTACs), linker proteins designed to bind specific bacterial proteins and target them for degradation by an endogenous intracellular protease. They will design and synthesize PROTACs against mycobacterial proteins of interest, then evaluate their activity using phenotypic assays with whole bacterial cells and using an ex vivo infected macrophage assay. They will characterize the mechanism of action of the PROTACs to assess their potency and guide iterative improvement. In parallel, they will also develop a screening platform, based on a cellular thermal shift assay (CETSA), to readily assess how well any PROTEC they design is able to penetrate mycobacterial cells and engage the specific target.

Collen Masimirembwa of the African Institute of Biomedical Science and Technology in Zimbabwe will establish a pan-African center of excellence focused on DMPK to support drug discovery and development in Africa. The center will perform DMPK assays and modeling to support two specific ongoing projects, one on antimalarial drug discovery led by Richard Amewu of the University of Ghana in Ghana with Lyn-Marie Birkholtz of the University of Pretoria in South Africa, and one on anti-TB drug development led by Erick Strauss of Stellenbosch University in South Africa. The center will establish a DMPK research network linking institutes and experts across the African continent to broadly support the discovery and development of safe and efficacious drugs for African populations. It will also provide training in DMPK for scientists through an annual workshop.

Richard Amewu of the University of Ghana in Ghana with Lyn-Marie Birkholtz of the University of Pretoria in South Africa will identify a lead candidate antimalarial drug with the potential to target multiple life cycle stages of the Plasmodium falciparum parasite. Drugs that not only target the parasite’s blood stage but also block parasite transmission can protect individuals from re-infection, decrease parasite prevalence, and prevent the spread of drug-resistant parasites. They will work as part of a research consortium across the African continent, integrating expertise in biology, medicinal chemistry, and drug metabolism and pharmacokinetics (DMPK). They will build on data from five classes of related compounds previously identified through antimalarial drug screening, seeking to identify an early lead candidate with a novel mechanism of action that can be further optimized.

Janine Aucamp of North-West University in South Africa will produce a novel drug screening platform for malaria by building a physiologically-relevant in vitro tissue model of the sinusoidal space of the human liver, which supports the development of liver-stage malaria parasites (sporozoites). Artemisinin-based combination therapies are first-line treatments for malaria but their efficacy suffers from the development of resistance, thus alternative approaches are needed. One approach is to block parasite development in the liver, which can prevent the establishment and symptomatic onset of malaria. They will build three different three-dimensional micro-bioreactor liver models and evaluate how well they can be infected by Plasmodium falciparum sporozoites compared to two-dimensional cultures. They will then test the value of the most promising model for identifying anti-malarial drugs first using two approved drugs and subsequently by screening novel drugs.

Grace Mugumbate of Chinhoyi University of Technology in Zimbabwe will develop new anti-malarial drugs by using a chemogenomics approach for ligand-based and structure-based virtual screening to identify compounds that selectively bind to heat shock proteins of the malaria parasite, Plasmodium falciparum. P. falciparum heat shock proteins are essential for parasite growth and survival, and represent a valuable new target for developing safe and effective anti-malarials. They will use existing chemical and genomic data to produce three-dimensional structures of several heat shock proteins for performing the virtual screens. Machine learning approaches will be used to identify binding ligands and inhibitors that will be validated using enzymatic assays in vitro. Promising hits will then be subjected to structure-based optimization to identify active compounds as leads for further development.

Erick Strauss of Stellenbosch University in South Africa will develop a small molecule inhibitor of an enzyme that helps pathogenic bacteria evade the host immune system and potentially become resistant to antibiotics as a novel treatment for methicillin-resistant S. aureus (MRSA), which is a major public health concern. They discovered a bacterial enzyme, MerA, that neutralizes an anti-microbial compound secreted by immune cells. This prolongs the survival of the bacteria in the host, giving them time to develop mutations that could render them less susceptible to antibiotics. They have identified two different chemical scaffolds that occupy the active site of MerA and will employ a new inhibitor discovery strategy that combines parallel synthesis with an X-ray structure-based binding screen to identify promising MerA inhibitor leads. These leads will be evaluated by in vitro and ex vivo assays for further development.

Lyn-Marie Birkholtz of the University of Pretoria in South Africa will identify gametocytocidal
compounds that specifically prevent human-to-mosquito transmission of gametocytes and block gamete and oocyst formation in mosquitoes as a complementary strategy to help eliminate malaria. Traditionally, anti-malarial compounds have been developed to target asexual blood-stage parasites. However, also blocking parasite transmission is critical for eradication. They developed a platform that can screen multiple sexual stages of the parasite and recently used it to identify ten hit compounds from the Medicines for Malaria Venture (MMV) Pandemic Response Box (PRB), most of which have not previously been tested against malaria-causing parasites. They will validate those hits, optimize them, and analyze their structure-activity-relationship (SAR) and their potential mode of action to identify at least one chemotype as an early lead candidate for further development.

Laurent Dembele of the Université des Sciences, des Techniques et des Technologies de Bamako in Mali will use their cell-based ex vivo phenotypic drug assay to identify approved anti-malarial drugs that are effective also against the neglected malaria-causing pathogen Plasmodium malariae, which has become widespread in sub-Saharan Africa. To eliminate malaria, treatments should be effective for all circulating malaria pathogens. However, current artemisinin-based combination therapies (ACTs) are largely designed to target the historically more prevalent P. falciparum species. They will recruit around 400 patients with uncomplicated malaria in Faladje to determine the P. malariae malaria burden. They will also evaluate the ability of a panel of anti-malarial compounds to destroy cultured P. malariae together with P. falciparum to help guide treatment strategies.

Fortunate Mokoena of North West University in South Africa will couple molecular docking approaches with in vitro and in vivo validation to identify novel inhibitors of Trypanosoma brucei and Plasmodium falciparum, the causative agents of the lethal diseases, African trypanosomiasis and malaria, respectively. Current drugs targeting these pathogens have limited efficacy due to the development of resistance and can cause severe side effects. They will identify a new group of drugs that specifically target parasitic molecular chaperone proteins, specifically heat shock protein 90 (Hsp90), which is an ATPase that helps correctly fold newly synthesized proteins. They will computationally model the structures of Hsp90 from both T. brucei and P. falciparum and prepare a three-dimensional database of inhibitors for virtual screening. The top 30 candidate inhibitors that selectively bind parasitic Hsp90 will be subjected to geometry optimization and induced fit molecular docking, followed by evaluation of their parasite killing activity in vivo.