Transcriptomics-Guided In Silico Drug Repurposing: Identifying New Candidates with Dual-Stage Antiplasmodial Activity

In tropical and subtropical
areas, malaria stands as a profound
public health challenge, causing an estimated 247 million cases worldwide
annually. Given the absence of a viable vaccine, the timely and effective
treatment of malaria remains a critical priority. However, the growing
resistance of parasites to currently utilized drugs underscores the
critical need for the identification of new antimalarial therapies.
Here, we aimed to identify potential new drug candidates against Plasmodium falciparum, the main causative agent of
malaria, by analyzing the transcriptomes of different life stages
of the parasite and identifying highly expressed genes. We searched
for genes that were expressed in all stages of the parasite’s
life cycle, including the asexual blood stage, gametocyte stage, liver
stage, and sexual stages in the insect vector, using transcriptomics
data from publicly available databases. From this analysis, we found
674 overlapping genes, including 409 essential ones. By searching
through drug target databases, we discovered 70 potential drug targets
and 75 associated bioactive compounds. We sought to expand this analysis
to similar compounds to known drugs. So, we found a list of 1557 similar
compounds, which we predicted as actives and inactives using previously
developed machine learning models against five life stages of Plasmodium spp. From this analysis, two compounds
were selected, and the reactions were experimentally evaluated. The
compounds HSP-990 and silvestrol aglycone showed potent inhibitory
activity at nanomolar concentrations against the P.
falciparum 3D7 strain asexual blood stage. Moreover,
silvestrol aglycone exhibited low cytotoxicity in mammalian cells,
transmission-blocking potential, and inhibitory activity comparable
to those of established antimalarials. These findings warrant further
investigation of silvestrol aglycone as a potential dual-acting antimalarial
and transmission-blocking candidate for malaria control.