The Water-Soluble [60]Fullerene Derivatives as Binders of SARS-CoV-2 Proteins

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-08-03 DOI:10.1021/acsmedchemlett.6c00282

Katarzyna Malarz, Tainah Dorina Marforio, Robert Gawecki, Dominik Dreszer, Matteo Calvaresi, Maciej Serda

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引用次数: 0

Abstract

Water-soluble fullerene derivatives represent emerging molecular nanomaterials for antiviral drug discovery, yet their target selectivity against SARS-CoV-2 proteins remains insufficiently defined. Here, four functionalized [60]fullerenes, C₆₀(OH)₂₄, C₆₀ser, C₆₀ALA, and C₆₀Trp, were evaluated as binders of key SARS-CoV-2 targets involved in viral entry and replication: spike glycoprotein, papain-like protease, 3CL main protease, and RNA-dependent RNA polymerase. Microscale thermophoresis revealed distinct target-dependent binding profiles governed by fullerene functionalization. The C₆₀Trp fullerene was the most active derivative, binding Spike with nanomolar affinity (K_d = 94.8 nM) and showing micromolar affinity toward papain-like protease and 3CL main protease. Docking and molecular dynamics simulations supported the preferential interaction of C₆₀Trp with the spike protein cavity through combined fullerene cage complementarity and polar interactions with lysine and arginine residues. The tested derivatives showed low cytotoxicity in A549 cells, and C₆₀Trp was efficiently internalized. These findings identify tryptophan-functionalized [60]fullerene as a promising multivalent scaffold for SARS-CoV-2 protein targeting.

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水溶性[60]富勒烯衍生物作为SARS-CoV-2蛋白结合物的研究

水溶性富勒烯衍生物是发现抗病毒药物的新兴分子纳米材料，但其对SARS-CoV-2蛋白的靶向选择性仍不充分确定。在这里，四种功能化的[60]富勒烯，C60(OH)24, C60ser， C60ALA和C60Trp，被评估为参与病毒进入和复制的关键SARS-CoV-2靶标的结合物：刺突糖蛋白，木瓜蛋白酶样蛋白酶，3CL主蛋白酶和RNA依赖性RNA聚合酶。微尺度热致电阻显示由富勒烯功能化控制的不同的靶依赖结合谱。C60Trp富勒烯是最活跃的衍生物，与Spike具有纳米摩尔亲和力（Kd =94.8 nM），对木瓜蛋白酶和3CL主蛋白酶具有微摩尔亲和力。对接和分子动力学模拟表明，C60Trp通过富勒烯笼互补和与赖氨酸和精氨酸残基的极性相互作用，支持了C60Trp与峰蛋白腔的优先相互作用。所测试的衍生物在A549细胞中显示出低的细胞毒性，并且C60Trp被有效地内化。这些发现确定了色氨酸功能化的[60]富勒烯是一种很有前途的靶向SARS-CoV-2蛋白的多价支架。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.