Author:
Bharti Hina,Singal Aakriti,Saini Manisha,Cheema Pradeep Singh,Raza Mohsin,Kundu Suman,Nag Alo
Abstract
AbstractMalaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.
Funder
University Grants Commission
Department of Science and Technology, Ministry of Science and Technology, India
Council of Scientific and Industrial Research, India
Department of Biotechnology, Ministry of Science and Technology, India
University of Delhi, India
University of Delhi
Publisher
Springer Science and Business Media LLC
Cited by
3 articles.
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