PDF(Pubmed)
Abstract：
Considering the high evolutionary rate and great harmfulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to develop new pharmacological antagonists. Human angiotensin-converting enzyme-2 (ACE2) functions as a primary receptor for the spike protein (S protein) of SARS-CoV-2. Thus, a novel functional peptide, KYPAY (K5), with a boomerang structure, was developed to inhibit the interaction between ACE2 and the S protein by attaching to the ACE2 ligand-binding domain (LBD). The inhibition property of K5 was evaluated via molecular simulations, cell experiments, and adsorption kinetics analysis. The molecular simulations showed that K5 had a high affinity for ACE2 but a low affinity for the cell membrane. The umbrella sampling (US) simulations revealed a significant enhancement in the binding potential of this functional peptide to ACE2. The fluorescence microscopy and cytotoxicity experiments showed that K5 effectively prevented the interaction between ACE2 and the S protein without causing any noticeable harm to cells. Further flow cytometry research indicated that K5 successfully hindered the interaction between ACE2 and the S protein, resulting in 78% inhibition at a concentration of 100 μM. This work offers an innovative perspective on the development of functional peptides for the prevention and therapy of SARS-CoV-2.
摘要：
考虑到严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的高进化率和极大的危害性，开发新的药物拮抗剂势在必行。人血管紧张素转换酶2（ACE2）作为SARS-CoV-2的刺突蛋白（S蛋白）的主要受体。因此，一种新的功能肽，KYPAY(K5),具有回旋镖结构，通过连接ACE2配体结合域（LBD）来抑制ACE2与S蛋白之间的相互作用。通过分子模拟评估K5的抑制性能，细胞实验,吸附动力学分析。分子模拟显示K5对ACE2具有高亲和力,但对细胞膜具有低亲和力。伞形取样(US)模拟显示该功能肽与ACE2的结合潜力显著增强。荧光显微镜和细胞毒性实验表明，K5有效地阻止了ACE2和S蛋白之间的相互作用，而不会对细胞造成任何明显的伤害。进一步的流式细胞术研究表明，K5成功地阻止了ACE2与S蛋白之间的相互作用，在100μM的浓度下产生78%的抑制。这项工作为预防和治疗SARS-CoV-2的功能肽的开发提供了创新的视角。
