Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Published: June 2017
AI Article Synopsis
Article Abstract
The sporogonic stage of the life cycle of spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis, and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. Efforts to cultivate mosquito stages have proved challenging and yielded only moderate success. Here, we describe a methodology that simplifies the screening of much-needed transmission-blocking (TB) compounds employing a bioluminescence-based method to monitor the development of sporogonic stages of the rodent malaria parasite Our proof-of-principle assessment of the TB activity of several commonly used antimalarial compounds identified cycloheximide, thiostrepton, and atovaquone as the most active compounds against the parasite's sporogonic stages. The TB activity of these compounds was further confirmed by studies that validated our newly developed approach to TB compound screening.
Novel antimalarial compounds targeting both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum, would greatly benefit malaria elimination strategies. However, most compounds affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact of this activity loss on a compound's transmission-blocking activity is unclear.
YAT2150 is a new antimalarial drug that shows promise for malaria treatment and diagnosis by increasing fluorescence upon entering cells and blocking key developmental stages in malaria pathogens.
The drug's effective uptake mechanisms and favorable pharmacokinetics make it a strong candidate for enhancing transmission-blocking strategies, especially when used in conjunction with immunoliposome encapsulation to reduce toxicity.
YAT2150 interacts preferentially with unstructured proteins in parasites, which may lead to decreased protein aggregation, a mechanism also seen with traditional antimalarial treatments, positioning it as a potential leader in innovative malaria therapies.
Background: Existing antimalarial drugs primarily target blood-stage parasites, but there is a need for transmission-blocking drugs to combat malaria effectively. Calcium-dependent Protein Kinase 4 (CDPK4) is a promising target for such drugs. This study employed advanced in silico analyses of hexahydroquinolines (HHQ) derivatives to identify CDPK4 inhibitors capable of disrupting malaria transmission.
Malaria remains a significant global health challenge due to the growing drug resistance of Plasmodium parasites and the failure to block transmission within human host. While machine learning (ML) and deep learning (DL) methods have shown promise in accelerating antimalarial drug discovery, the performance of deep learning models based on molecular graph and other co-representation approaches warrants further exploration. Current research has overlooked mutant strains of the malaria parasite with varying degrees of sensitivity or resistance, and has not covered the prediction of inhibitory activities across the three major life cycle stages (liver, asexual blood, and gametocyte) within the human host, which is crucial for both treatment and transmission blocking.
