Srabani Roy Chowdhury (MAKAUT, WB)
Despite all the global malaria control measures, more than a 200million malaria cases are seen, out of which 0.5million people have succumbed to death. The attempts for new drugs have led to the identification of various chemical compounds that can destroy the parasites in the different stages of their life cycle. This will not only help in prevention but also in the treatment of the disease. The Malaria Drug Accelerator (MalDA) consortium prescribed to solve the target identification problems were to be solved by chemo-genomic approaches. To understand liver-stage activity and identify chemical scaffolds with liver-stage activity, more than 500,000 compounds were screened. The whole-cell phenotypic screening was used to identify many such anti-malarial compounds. These compounds that showed activity under phenotypic screening target the common pathways like mitochondrial function, haemoglobin degradation, cellular homeostasis in the parasite with common resistance mechanisms.
Results
- MMV019721 and MMV084978 were found to effectively inhibit asexual- and liver-stage growth
MMV019721 and MMV084978 are two small molecules found in whole-cell sequencing. They are effective against multiple parasite life-cycle stages like liver and asexual blood stages. It indicated that these compounds can be used for both chemo-prophylactic and curative therapeutic applications. These compounds suggested a new pathway since they were not cross-resistant with any of the targets identified previously. MMV019721 has self-effacing activity against both blood-stage and liver-stage parasites. MMV084978 also showed similar activity but had increased potency for liver-stage parasites.
- Acetyl-CoA biosynthesis targeted by MMV019721 and MMV084978
In vitro evolutionary experiments were conducted to identify and select resistant parasites as the targets of MMV019721 and MMV084978. Homology modeling of P. falciparum shows that the active site of the enzyme can be predicted by the mutations present in the parasites resistant to MMV019721 or MMV084978. Acetyl-CoA synthetase in these mutations provides resistance to MMV019721 and MMV084978.
- Parasite growth subsides due to PfAcAS knockdown and causes differential sensitivity to MMV019721 and MMV084978
Genetic mutations discovered contain drug resistance genes. Hypersensitivity of both MMV019721 and MMV084978 was induced by Low aTc or reduced PfAcAS expression. Growths over two replicative cycles were analyzed. It was observed that withdrawal of aTc led to substantial growth arrest. However, maintenance of the parasites in presence of aTc showed progression in their life cycle.
- Allelic replacement studies were conducted. These studies showed that for resistance to MMV019721 and MMV084978 the PfAcAS mutations are sufficient.
Conclusion
In this study, Acetyl-CoA synthetase has been identified as a drug target in P. falciparum. In vitro, evolutionary resistance experiments were conducted to identify mutations in the PfAcAS gene. Allelic replacement of resistance mutations into a wild-type parasite-induced genetic validation. This confirmed sufficient resistance in each mutation in PfAcAS. Not only the TCA cycle, lipid, and phospholipid synthesis, Acetyl-CoA is central to many cellular pathways. Considering an impact on these pathways is very important. Newly identified drug targets are essential for malaria treatment, prevention, and eradication. These drug targets will have activity against multiple stages of the parasite so that they can induce chemo-protective or transmission-blocking effects along with its therapeutic activity. This is why the identification and validation of these novel drug targets are considered to be a crucial priority.
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Reference
Summers, R. L., Pasaje, C. F. A., Pisco, J. P., Striepen, J., Luth, M. R., Kumpornsin, K., Carpenter, E. F., Munro, J. T., Lin, D., Plater, A., Punekar, A. S., Shepherd, A. M., Shepherd, S. M., Vanaerschot, M., Murithi, J. M., Rubiano, K., Akidil, A., Ottilie, S., Mittal, N., … Lukens, A. K. (2021). Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chemical Biology, S2451945621003500. https://doi.org/10.1016/j.chembiol.2021.07.010
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