ArticleScientific reports2018
Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?Current medicinal chemistry · 2024Review
- Microsecond-long simulation reveals the molecular mechanism for the dual inhibition of falcipain-2 and falcipain-3 by antimalarial lead compounds.Frontiers in molecular biosciences · 2022Article
- In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2.Journal of computer-aided molecular design · 2021Article
- Cohnella 1759 cysteine protease shows significant long term half-life and impressive increased activity in presence of some chemical reagents.Scientific reports · 2021Article
- Structural Insights Into KeyFrontiers in microbiology · 2019Review
- Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Falcipains are major haemoglobinases of Plasmodium falciparum required for parasite growth and development. They consist of pro- and mature domains that interact via 'hot-spot' interactions and maintain the structural integrity of enzyme in zymogen state. Upon sensing the acidic environment, these interactions dissociate and active enzyme is released. For inhibiting falcipains, several active site inhibitors exist, however, compounds that target via allosteric mechanism remains uncharacterized. Therefore, we designed and synthesized six azapeptide compounds, among which, NA-01 & NA-03 arrested parasite growth by specifically blocking the auto-processing of falcipains. Inhibitors showed high affinity for enzymes in presence of the prodomain without affecting the secondary structure. Binding of NA-03 at the interface induced rigidity in the prodomain preventing structural reorganization. We further reported a histidine-dependent activation of falcipain. Collectively, for the first time we provide a framework for blocking the allosteric site of crucial haemoglobinases of the human malaria parasite. Targeting the allosteric site could provide high selectivity and less vulnerable to drug resistance.
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Registered trials
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