Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea.
Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea.
Sci Adv. 2022 Oct 28;8(43):eabq6207. doi: 10.1126/sciadv.abq6207. Epub 2022 Oct 26.
The frequent occurrence of viral variants is a critical problem in developing antiviral prophylaxis and therapy; along with stronger recognition of host cell receptors, the variants evade the immune system-based vaccines and neutralizing agents more easily. In this work, we focus on enhanced receptor binding of viral variants and demonstrate generation of receptor-mimicking synthetic reagents, capable of strongly interacting with viruses and their variants. The hotspot interaction of viruses with receptor-derived short peptides is maximized by aptamer-like scaffolds, the compact and stable architectures of which can be in vitro selected from a myriad of the hotspot peptide-coupled random nucleic acids. We successfully created the human angiotensin-converting enzyme 2 (hACE2) receptor-mimicking hybrid ligand that recruits the hACE2-derived receptor binding domain-interacting peptide to directly interact with a binding hotspot of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Experiencing affinity boosting by ~500% to Omicron, the de novo selected hACE2 mimic exhibited a great binding tolerance to all SARS-CoV-2 variants of concern.
病毒变体的频繁出现是开发抗病毒预防和治疗方法的一个关键问题；随着对宿主细胞受体的认识不断增强，这些变体更容易逃避基于免疫系统的疫苗和中和剂。在这项工作中，我们专注于增强病毒变体的受体结合，并展示了受体模拟合成试剂的产生，这些试剂能够与病毒及其变体强烈相互作用。通过适体样支架最大化了病毒与受体衍生的短肽的热点相互作用，其紧凑和稳定的结构可以从大量热点肽偶联的随机核酸中体外选择。我们成功地创建了人血管紧张素转换酶 2（hACE2）受体模拟杂交配体，该配体募集 hACE2 衍生的受体结合域相互作用肽，直接与严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的结合热点相互作用。新选择的 hACE2 模拟物对奥密克戎的亲和力提高了约 500%，对所有受关注的 SARS-CoV-2 变体表现出很强的结合耐受性。
