Focus Areas and Objectives

The CoP will continue to focus on malaria elimination with the aim to critically evaluate malaria control interventions to support malaria elimination strategies. The CoP combines the expertise of 6 SARChI Chairs to provide novel small molecules able to block human-to-mosquito malaria transmission and thereby contribute to the global pipeline of drug leads aimed at malaria elimination.

The objectives of the CoP are based on 3 inter-dependent focus areas, each with their own individual projects led by a SARChI Chair:

1) Identification of novel antimalarial lead molecules with activity against the asexual blood stage forms of the human malaria parasite Plasmodium falciparum

2) Evaluation of the ability of the identified lead molecules to kill malaria parasite transmissible gametocytes

3) Evaluation of lead compounds to block human-to-mosquito transmission of malaria parasites

4) Evaluation of novel systems to improve delivery of lead molecules

5) Predicting the efficacy of the above interventions in various malaria elimination settings by building and analyzing mathematical models.

Focus area 1: Drug Discovery and its applications on malaria parasites and mosquito vectors

Project 1: Dual Acting Asexual Blood Stage and Transmission-Blocking Antimalarials. (Prof K Chibale)

This project will focus on identifying novel chemical entities initially with P. falciparum asexual blood stage (ABS) activity, which will be evaluated in project 2 (for transmission-blocking activity), project 3 (for their ability to block human-to-mosquito transmission in case of those that also show transmission-blocking activity) and in project 4 (for targeted delivery and release in infected red blood cells in case of those also show transmission-blocking activity). Compounds showing both ABS and transmission-blocking activities will also be evaluated for their ability to kill liver stage parasites (collaboration with Malaria Drug Accelerator, MalDA). Both target- and phenotypic whole cell screening-based approaches will be undertaken.

Project 2: Antimalarial agents that target parasites for transmission-blocking activity. (Prof L Birkholtz)

This project will focus evaluate the ability of novel compounds from project 1 to kill the transmissible gametocytes of P. falciparum parasites. Additional chemical matter will also be evaluated from other partners, including artemisinins (collaboration with Prof R Haynes (NWU), drugs targeting the parasite’s epigenome as well as novel plant extracts (collaboration with Prof V Maharaj, UP and Prof G Bringman, Germany). All compounds are progressed through a unique 3-tiered gametocytocidal hit screening cascade developed by the SAMTC and MMV (Birkholtz et al., 2016). This includes counter-screens and downstream high-information content ex vivo assays for triaging. As part of the strategic planning for roll-out of transmission-blocking drugs, genotyping of South African P. falciparum field isolates for primaquine and artemisinin resistance will also be performed.

Project 3: Blocking human to mosquito transmission. (Prof L Koekemoer)

This project will aim to evaluate the transmission-blocking activity of novel compounds from project 2 on African malaria vectors. A reduction in parasite prevalence, oocyst intensity and sporogeny are used as indicators of efficacy. In addition, the current application will also evaluate the newly established endectocide platform on selected compounds. Endectocides able to reduce vector longevity will prevent the development of parasites to the infectious sporozoites and hence block transmission. Potentially active compounds will be tested on wild vector mosquitoes collected in northern KwaZulu/Natal. A mosquito contact based assay (Paton et al., 2019) with lead compounds the to block internal sporozoite development within mosquitoes will also be performed as a novel strategy to block transmission.

Focus area 2: Drug Delivery and its therapeutic use, linked to above to improve/modify Interventions

Project 4: Antimalarial drug delivery systems. (Prof B Klumperman)

This project aims to develop a targeted drug delivery platform to erythrocytes infected with malaria parasites. Focus will be on precise amphiphilicity control, triggered drug release, and self- assembly of the drug-loaded delivery system for erythrocyte uptake.

Focus area 3: Modelling of elimination scenarios

Project 5: Modelling the parasite metabolic response to drug treatment. (Prof J Snoep)

The experimental data from the lead compounds identified from different projects will be utilized for generating detailed mathematical models to analyse the effect on the metabolism of the parasite, human cells and at the whole-body level, particularly that of glucose metabolism and later on include host immune responses. In the initial stages these model simulations can give valuable information on the mode of action of the drug, and at later stages to analyse side-effects in the host.

Project 6: Advanced mathematical models for malaria control. (Prof J Banasiak)

The aim will be to develop mathematical models to formulate a theoretical framework to comprehensively analyse models to gain a better understanding of the complex web of interactions in malaria transmission and to provide a foundation for more informed decision making. The work will be done in collaboration with Dr R Ouifki (UP) and USA and Cameroonian experts (Prof M. Teboh-Ewungkem and Prof G Ngwa). Also, a former PhD student of Prof Ngwa, Assefa Woldegebriel, is joining J. Banasiak in October 2019.