Kalihinol Analog Targets Apicoplast Function In Malaria Treatment
Karine G. Le Roch, PhD, discussed her research on a kalihinol analog that combats drug resistance in malaria, emphasizing the need for innovative treatments in the context of climate change and rising transmission rates.
At IDWeek 2024, Karine G. Le Roch, PhD, professor in the Department of Molecular, Cell, and Systems Biology at the University of California, presented her research on a kalihinol analog targeting apicoplast function in Plasmodium falciparum. Le Roch’s research focuses on understanding cellular processes and molecular interactions, often using innovative techniques to explore complex biological systems. This research is relevant due to increasing drug resistance in malaria treatment.
In our interview at IDWeek, Le Roch explained, “I've been working on natural products, specifically a molecule extracted from marine sponges in the 1990s, but we didn't fully understand its mechanism of action. We know this family of compounds is effective against various pathogens, including Plasmodium and fungi, with Plasmodium falciparum being the human malaria parasite responsible for infections.”
To build on this, she noted, “Our focus has been on creating simplified analogs of this initial natural product to produce larger quantities and identify the drug's mechanism of action. Many natural products are effective, but we must ensure they are not toxic to humans and understand how they work.”
Le Roch further highlighted the significance of her research, “By developing a new research pipeline in systems biology, we identified the mechanism of action for a new semi-synthetic compound that targets the malaria parasite. This compound affects several pathways in the Apicomplexa, which is a group of parasites that includes Plasmodium. The Apicomplexa contains a unique organelle crucial for producing metabolites essential for lipid pathways in Plasmodium, and it does not exist in humans. It's exciting to target something that is specific to the parasite and does not affect humans.”
She then addressed the issue of drug resistance, “Additionally, this natural product interacts with multiple pathways, making it difficult for the parasite to develop resistance, unlike chloroquine, which targets a limited number of pathways, mainly the food vacuole. Recently, this new semi-synthetic compound has shown effectiveness in targeting the Apicomplexa organelle and influencing various trafficking processes, making it harder for the parasite to become resistant compared to chloroquine.”
We discussed how climate change could influence malaria transmission and treatment effectiveness. “With global warming, we're seeing an increase in mosquito populations, even in Southern California, where there weren't many mosquitoes 20 years ago. The presence of these mosquitoes means the likelihood of malaria returning to developed countries is higher. Increased transmission of infections leads to a rise in circulating pathogens, which can also lead to increased resistance. As transmission grows, the demand for new drugs to target these parasites becomes more urgent.”
Le Roch then discussed the current landscape of drug development, “Currently, we have many molecules available, but they often target the same molecular pathways. Since the parasite has developed resistance to these pathways, identifying new drugs that target different pathways can lower the chances of resistance. By combining several molecules, we can further decrease the likelihood of the parasite becoming resistant.”
We discussed the next steps for this research on the kalihinol analog and its potential role in malaria control and eradication. “We still need to simplify the compound. It's a semi-synthetic product derived from a natural source, but it's currently too complex for widespread use. For a compound targeting a disease that predominantly affects people in poorer countries, we must find ways to simplify its synthesis and create a more affordable version. So far, it shows promise as a treatment, but it remains too expensive for a disease of this nature.” Le Roch's research on the kalihinol analog provides a potential new option for treating malaria and addresses challenges related to drug resistance.
