Page 126 - SAMRC Annual Report 2024-2025

Drug Discovery &
Development Research Unit

Unit director:
Prof. Kelly Chibale

Kelly.Chibale@uct.ac.za

Advancing Research Priorities: over multiple days. Doing so would also lower the
Strategic Objectives and Impact maximum drug concentration, which is important for
addressing toxicity concerns.
The Drug Discovery and Development Research
Unit's top priority in the reporting period was 2-fold: In terms of the second priority, we identified and
reported on a potent series of acyl-thiourea platinum
First, to understand whether the efficacy of the (II) complexes with dual-stage anti-plasmodium
anti-malarial drug candidate is driven by time or activity and promising pharmacological properties
concentration above a defined threshold. This that appear to act via a novel mechanism of action,
enabled the selection of dosing regimens that or via polypharmacology. Further mechanism of
would optimize clinical efficacy while suppressing resistance studies for lead compounds in this series
the emergence of resistant malaria parasites and have led to the discovery of a pathway in Plasmodium
toxicity. Second, to identify quality leads suitable for falciparum that is being investigated as a potential
optimisation as potential agents for the treatment new anti-malarial drug target.
of uncomplicated Plasmodium falciparum malaria,
ideally with additional activity against gametocytes, Building Capacity Through
the transmissible forms of the parasite.
Training, Mentorship, and Support
Key Milestones and Achievements The Unit, in partnership with the H3D Foundation,

In terms of priority, using the Plasmodium falciparum concluded a fruitful year of capacity-building and
training initiatives. This included the formalisation
humanised mouse model, we conducted drug of the Grand Challenges African Drug Discovery
dose fractionation studies, i.e. fractionation of a
drug dose over multiple days. We investigated the
Pharmacokinetic/Pharmacodynamic relationships
of UCT594 relative to blood stage activity towards
predicting the human dose. UCT594 demonstrated
concentration-dependent killing. Using this data
and the pre-clinical pharmacokinetic data led to a
low predicted human dose of < 50 mg. The results
suggested concentration-dependent killing is more
likely to afford a better clinical result than maximizing
time of exposure. The significance of this finding is
that the preference within the malaria community
is towards a single-dose oral drug that delivers a
cure to ensure maximum compliance, but it may
not be predicted to be optimal for efficacy by the
dose fractionation study in the humanised mouse.
The preference would be fractionation of the dose

124 SAMRC ANNUAL REPOR T 2024-25