Journal Article Ahead of print
PubMed: 40946223 DOI: 10.1002/cmdc.202500282
Targeting Plasmodium falciparum Single-Stranded DNA-Binding Protein: Discovery of New Scaffold Compounds Effective against Drug-Sensitive and Artemisinin-Resistant Strains.
ChemMedChem
Authors: Biswajit Naik, Preshita Bhalerao, Shashank Shekhar, Stephy A Varghese, Sweta Makwana, Chandi C Mandal, Tarun Kumar Bhatt, Suman Kumar Dhar, Dhaneswar Prusty
Affiliations
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India.
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India.
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
- TERI School of Advanced Studies Institutional Area, Vasant Kunj, New Delhi, 110070, India.
Abstract
Resistance to frontline antimalarials by malaria parasites is a major concern, prompting the search for novel antimalarial compounds targeting new drug targets. One promising target is the single-stranded DNA-binding protein (PfSSB) of Plasmodium falciparum, crucial for DNA replication process in apicoplast, an essential organelle. Using an integrative approach, PPG and 9-HPF are identified, which inhibit the DNA binding property of PfSSB and exhibit antimalarial activity. Computational analyses reveal that both compounds possess strong binding affinity and favorable drug-like properties. Biolayer interferometry assay and the gel retardation assays demonstrate that they have a stronger binding affinity and disrupt PfSSB's ssDNA binding ability. PPG and 9-HPF show antimalarial activity against drug-sensitive P. falciparum (3D7) with IC 50 values of 54.95 and 9.13 μM, respectively, and they can also effectively inhibit artemisinin-resistant P. falciparum (C580Y) with a resistance index of 0.79 and 1.26, respectively. MTT cytotoxicity assays confirm that both compounds are nontoxic, and structural similarity analysis indicates that they are distinct from existing antimalarials, reducing cross-resistance risk. Additionally, virtual screening of 59,807 compounds with similar structures to PPG and 9-HPF identifies candidates with higher affinities for PfSSB. This study identifies PPG and 9-HPF as structurally distinct antimalarials with the potential to combat drug-resistant P. falciparum.
MeSH
Malaria, Pharmaceutical Preparations, Dna-Binding Proteins, Dna, Single-Stranded, Antimalarials, Dna, Drug Resistance