Biology subjects

van der Watt, M.

Publications and source records attributed to van der Watt, M..

4 recordsLinked to original sources

bioRxiv2025

The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity Against Plasmodium falciparum via Dual Inhibition of PfArk1 and Hemozoin Formation

The high burden of malaria and growing resistance to frontline antimalarials demand new drug target combinations with reduced propensities for conferring parasite resistance. An attractive approach for circumventing antimalarial drug resistance is target repurposing in which known drugs that act through protein targets of human origin that are also active against the human malaria parasite Plasmodium falciparum are exploited to identify novel antimalarial drug targets. Here we show that the human checkpoint kinase 1 (Chk1) inhibitor CHIR-124 is active in vitro against both drug-sensitive and drug-resistant asexual blood stage parasites and competitively binds to several Plasmodium kinases. The compound also shows moderate activity against both the liver and gametocyte forms of the parasite. Further target investigation of CHIR-124 via conditional knockdown experiments confirmed that P. falciparum Aurora-related kinase 1 (PfArk1) is implicated in its parasiticidal activity. Notably, CHIR-124 also inhibits {beta}-hematin (synthetic hemozoin) formation and causes a dose-dependent increase in free heme that correlates with inhibition of parasite growth. These findings suggest that polypharmacology is involved in the activity of CHIR-124 against P. falciparum via the dual inhibition of Plasmodium PfArk1 and hemozoin formation, both essential for parasite proliferation. This is further supported by in vitro drug combination experiments, morphological studies and resistance generation attempts. This study validates the feasibility of dual Plasmodium kinase/hemozoin formation inhibitors active against resistant strains with decreased resistance risks in the fight against malaria.

microbiology↗

bioRxiv2023

Genetic complexity alters drug susceptibility of asexual and gametocyte stages of Plasmodium falciparum to antimalarial candidates

Withdrawal statementThe authors have withdrawn their manuscript owing to internal reviewing and agreement to submission by all parties involved in the work not yet completed on this version of the paper. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

biochemistry↗

bioRxiv2022

Molecular autism research in Africa: a scoping review comparing publication outputs to Brazil, India, the UK, and the USA.

The increased awareness of autism spectrum disorders (ASD) is accompanied by burgeoning ASD research, and concerted research efforts are trying to elucidate the molecular ASD aetiology. However, much of this research is concentrated in the Global North, with recent reviews of research in Sub-Saharan Africa (SSA) highlighting the significant shortage of ASD publications from this region. The most limited focus area was molecular research with only two molecular studies ever published from SSA, both being from South Africa (SA). We examine the molecular ASD research publications from 2016 to 2021 from all African countries, with a special focus on SA. The SSA publications are compared to Brazil and India, two non-African, low-to-middle-income countries (LMICs), and to the UK and USA, two high-income countries (HICs). There were 228 publications across all regions of interest; only three publications were from SA. Brazil (n=29) and India (n=27) had almost 10 times more publications than SA. The HICs had more publications than the LMICs, with the UK (n=62) and the USA (n=74) having approximately 20 to 25 times more publications than SA, respectively. Given that SA has substantial research capacity as demonstrated by its recent research on SARS-CoV-2, we explore potential reasons for this deficit in molecular ASD publications from SA. We compare mental health research outputs, GDP per capita, research and development expenditure, and the number of psychiatrists and child psychiatrists per 100,000 people across all regions. The UK and the USA had significantly higher numbers for all these indicators, consistent with their higher publication output. Among the LMICs, SA can potentially produce more molecular ASD research, however, there are numerous barriers that need to be addressed to facilitate increased research capacity. These include cultural stigmas, challenges in accessing mental healthcare, shortages of specialists in the public sector, and the unreliability of ASD diagnostic tools across the 11 official SA languages. The unique genetic architecture of African populations presents an untapped reservoir for finding novel genetic loci associated with ASD. Therefore, addressing the disparity in molecular ASD research between the Global North and SSA is integral to global advancements in ASD research.

molecular biology↗

bioRxiv2019

Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites

The epigenome of the malaria parasite, Plasmodium falciparum, is associated with control of various essential processes in the parasite including control of proliferation of asexual development as well as sexual differentiation. The unusual nature of the epigenome has prompted investigations of the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity associated with a library of 95 compounds, active against various epigenetic modifiers within cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and non-histone epigenetic modifiers. Moreover, 4 compounds targeting histone acetylation and methylation, show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds.

biochemistry↗