Dendrimer-Peptide Conjugates for Effective Blockade of the Interactions between SARS-CoV-2 Spike Protein and Human ACE2 Receptor
Dendrimer-Peptide Conjugates for Effective Blockade of the Interactions between SARS-CoV-2 Spike Protein and Human ACE2 Receptor
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DOI：
10.1021/acs.biomac.2c01018
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发表时间：
2022-12-23
影响因子：
6.2
通讯作者：
Hong, Seungpyo
中科院分区：
文献类型：
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作者：
Jeong, Woo-jin;Bu, Jiyoon;Hong, Seungpyo
2019冠状病毒病（COVID-19）大流行威胁到全球医疗保健的稳定，这正在成为一个地方性问题。尽管开发了各种治疗策略来对抗COVID-19，但目前可用的治疗方案显示出不同的疗效。在此，我们开发了一种基于亲和力的SARS-CoV-2拮抗剂，使用树突状肽偶联物（DPCs）有效治疗COVID-19。从血管紧张素转换酶2 （ACE2）中获得的两个不同的肽片段被整合到一个序列中，然后结合到聚氨基胺（PAMAM）树状大分子上。我们假设树状大分子所赋予的强多价结合亲合力将有助于多肽有效地阻断SARS-CoV-2与ACE2之间的相互作用，并且这种拮抗作用将取决于树状大分子的产生（大小）。为了评估这一点，利用表面等离子体共振定量测量了第4代（G4）和G7 PAMAM树突状分子制备的DPCs与SARS-CoV-2刺突蛋白的结合动力学。与游离肽相比，较大的树突基DPCs的结合强度显著提高了3个数量级，而较小的树突基DPCs的结合强度仅提高了12.8倍。利用模拟SARS-CoV-2微珠进行的体外实验也显示，与G4相比，g7肽偶联物的SARS-CoV-2阻断效率有所提高。此外，利用分子动力学（MD）模拟分析了DPCs与SARS-CoV-2之间的相互作用，从而深入了解树突分子介导的多价结合效应如何增强SARS-CoV-2的阻断作用。我们的研究结果表明，与SARS-CoV-2具有强结合的DPCs有效地阻断了ACE2和SARS-CoV-2之间的相互作用，提供了作为高亲和力药物递送系统直接抗covid有效载荷到病毒的潜力。
The coronavirus disease 2019 (COVID-19) pandemic has threatened the stability of global healthcare, which is becoming an endemic issue. Despite the development of various treatment strategies to fight COVID-19, the currently available treatment options have shown varied efficacy. Herein, we have developed an avidity-based SARS-CoV-2 antagonist using dendrimer-peptide conjugates (DPCs) for effective COVID-19 treatment. Two different peptide fragments obtained from angiotensin-converting enzyme 2 (ACE2) were integrated into a single sequence, followed by the conjugation to poly(amidoamine) (PAMAM) dendrimers. We hypothesized that the strong multivalent binding avidity endowed by dendrimers would help peptides effectively block the interaction between SARS-CoV-2 and ACE2, and this antagonist effect would be dependent upon the generation (size) of the dendrimers. To assess this, binding kinetics of the DPCs prepared from generation 4 (G4) and G7 PAMAM dendrimers to spike protein of SARS-CoV-2 were quantitatively measured using surface plasmon resonance. The larger dendrimer-based DPCs exhibited significantly enhanced binding strength by 3 orders of magnitude compared to the free peptides, whereas the smaller one showed a 12.8-fold increase only. An in vitro assay using SARS-CoV-2-mimicking microbeads also showed the improved SARS-CoV-2 blockade efficiency of the G7-peptide conjugates compared to G4. In addition, the interaction between the DPCs and SARS-CoV-2 was analyzed using molecular dynamics (MD) simulation, providing an insight into how the dendrimer-mediated multivalent binding effect can enhance the SARS-CoV-2 blockade. Our findings demonstrate that the DPCs having strong binding to SARS-CoV-2 effectively block the interaction between ACE2 and SARS-CoV-2, providing a potential as a high-affinity drug delivery system to direct anti-COVID payloads to the virus.