Targeting Plasmodium falciparum Single-Stranded DNA-Binding Protein: Discovery of New Scaffold Compounds Effective against Drug-Sensitive and Artemisinin-Resistant Strains.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-14 DOI:10.1002/cmdc.202500282
Biswajit Naik, Preshita Bhalerao, Shashank Shekhar, Stephy A Varghese, Sweta Makwana, Chandi C Mandal, Tarun Kumar Bhatt, Suman Kumar Dhar, Dhaneswar Prusty
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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 IC50 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.

靶向恶性疟原虫单链dna结合蛋白:发现对药物敏感和耐青蒿素菌株有效的新支架化合物。
疟疾寄生虫对一线抗疟药物的耐药性是一个主要问题,这促使人们寻找针对新药靶点的新型抗疟化合物。恶性疟原虫(Plasmodium falciparum)的单链DNA结合蛋白(PfSSB)是一个很有希望的靶标,它对重要细胞器顶质体的DNA复制过程至关重要。采用综合方法鉴定了PPG和9-HPF,它们抑制PfSSB的DNA结合特性并表现出抗疟疾活性。计算分析表明,这两种化合物都具有很强的结合亲和力和良好的药物性质。生物层干涉实验和凝胶阻滞实验表明,它们具有较强的结合亲和力,破坏了PfSSB的ssDNA结合能力。PPG和9-HPF对药物敏感型恶性疟原虫3D7 (IC50值分别为54.95和9.13 μM)具有抗疟活性,对耐青蒿素型恶性疟原虫C580Y(耐药指数分别为0.79和1.26)也有较好的抑制作用。MTT细胞毒性试验证实这两种化合物都是无毒的,结构相似性分析表明它们与现有的抗疟药不同,从而降低了交叉耐药风险。此外,对59,807个与PPG和9-HPF结构相似的化合物进行虚拟筛选,确定了与PfSSB具有较高亲和力的候选化合物。本研究确定PPG和9-HPF是结构上不同的抗疟药,具有对抗耐药恶性疟原虫的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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