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.

 

Comments:

Your description outlines a comprehensive research effort to identify potential new drug candidates against Plasmodium falciparum, the causative agent of malaria. The research approach combines advanced bioinformatics techniques with experimental validation, highlighting the multidisciplinary nature of drug discovery.

Here's a breakdown of the key points from your research:

### Objective:
- **Identification of new antimalarial therapies** due to the growing resistance of parasites to current drugs.

### Methodology:
1. **Transcriptome Analysis:**
   - Studied different life stages of the parasite.
   - Analyzed highly expressed genes across all stages.
   - Identified 674 overlapping genes, including 409 essential ones.

2. **Drug Target Identification:**
   - Searched for potential drug targets using databases.
   - Discovered 70 potential drug targets and 75 associated bioactive compounds.

3. **Expansion of Analysis:**
   - Identified 1557 similar compounds to known drugs.
   - Utilized machine learning models against various Plasmodium spp. life stages.

4. **Experimental Validation:**
   - Selected two compounds, **HSP-990 and silvestrol aglycone**, based on computational predictions.
   - Experimentally evaluated their inhibitory activity against the P. falciparum 3D7 strain asexual blood stage.

### Results:
- **Efficacy:** Both compounds showed potent inhibitory activity at nanomolar concentrations against the asexual blood stage of P. falciparum.
- **Safety:** Silvestrol aglycone exhibited low cytotoxicity in mammalian cells, indicating potential safety.
- **Transmission-Blocking Potential:** Silvestrol aglycone demonstrated transmission-blocking potential.
- **Comparison:** Silvestrol aglycone’s inhibitory activity was comparable to established antimalarials.

### Implications:
- **Potential Dual-Acting Antimalarial:** Silvestrol aglycone emerges as a potential dual-acting antimalarial and transmission-blocking candidate.
- **Future Research:** Warrants further investigation and development for malaria control strategies.

This research is significant as it not only identifies potential drug candidates but also emphasizes the importance of a multidisciplinary approach, combining bioinformatics, computational modeling, and experimental validation in the drug discovery process. The findings pave the way for further studies and potential advancements in malaria treatment and prevention.

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Apoptosis related HSP (HSP90)