DataSheet1_Improvement of native structure-based peptides as efficient inhibitors of protein-protein interactions of SARS-CoV-2 spike protein and human ACE2.PDF

New pathogens responsible for novel human disease outbreaks in the last two decades are mainly the respiratory system viruses. Not different was the last pandemic episode, caused by infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One of the extensively explored targets, in the recent scientific literature, as a possible way for rapid development of COVID-19 specific drug(s) is the interaction between the receptor-binding domain of the virus’ spike (S) glycoprotein and human receptor angiotensin-converting enzyme 2 (hACE2). This protein-protein recognition process is involved in the early stages of the SARS-CoV-2 life cycle leading to the host cell membrane penetration. Thus, disrupting this interaction may block or significantly reduce the infection caused by the novel pathogen. Previously we have designed (by in silico structure-based analysis) three very short peptides having sequences inspirited by hACE2 native fragments, which effectively bind to the SARS-CoV-2 S protein and block its interaction with the human receptor. In continuation of the above mentioned studies, here we presented an application of molecular modeling approach resulting in improved binding affinity of the previously proposed ligand and its enhanced ability to inhibit meaningful host-virus protein-protein interaction. The new optimized hexapeptide binds to the virus protein with affinity one magnitude higher than the initial ligand and, as a very short peptide, has also great potential for further drug development. The peptide-based strategy is rapid and cost-effective for developing and optimizing efficient protein-protein interactions disruptors and may be successfully applied to discover antiviral candidates against other future emerging human viral infections.

近二十年来，引发新型人类疾病暴发的新型病原体主要为呼吸道病毒。刚刚过去的新冠大流行亦不例外，其由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染所致。近年来，科研文献中被广泛探索的、有望快速开发新型冠状病毒肺炎（COVID-19）特异性药物的靶点之一，是病毒刺突（S）糖蛋白的受体结合域与人类受体血管紧张素转换酶2（hACE2）之间的相互作用。该蛋白质-蛋白质识别过程参与SARS-CoV-2生命周期的早期阶段，介导宿主细胞膜的侵入。因此，阻断这一相互作用可阻断或显著降低该新型病原体引发的感染。此前，我们通过基于虚拟计算的结构分析（in silico structure-based analysis）设计了三条序列灵感源自hACE2天然片段的超短肽，它们可有效结合SARS-CoV-2的S蛋白并阻断其与人类受体的相互作用。在上述研究的延续工作中，本文展示了分子建模方法的应用，该方法可提升此前提出的配体的结合亲和力，并增强其抑制有效宿主-病毒蛋白质-蛋白质相互作用的能力。新优化的六肽与病毒蛋白的结合亲和力较初始配体高一个数量级，且作为超短肽，其在后续药物开发中也具备巨大潜力。基于肽的开发策略可快速且低成本地开发和优化高效的蛋白质-蛋白质相互作用阻断剂，且可成功应用于发现针对未来其他新型人类病毒感染的抗病毒候选药物。