Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
PLoS One. 2023 Oct 24;18(10):e0293263. doi: 10.1371/journal.pone.0293263. eCollection 2023.
The COVID-19 pandemic has created an urgent need for effective therapeutic and diagnostic strategies to manage the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the emergence of numerous variants of concern (VOCs) has made it challenging to develop targeted therapies that are broadly specific in neutralizing the virus. In this study, we aimed to develop neutralizing nanobodies (Nbs) using computational techniques that can effectively neutralize the receptor-binding domain (RBD) of SARS-CoV-2 VOCs. We evaluated the performance of different protein-protein docking programs and identified HDOCK as the most suitable program for Nb/RBD docking with high accuracy. Using this approach, we designed 14 novel Nbs with high binding affinity to the VOC RBDs. The Nbs were engineered with mutated amino acids that interacted with key amino acids of the RBDs, resulting in higher binding affinity than human angiotensin-converting enzyme 2 (ACE2) and other viral RBDs or haemagglutinins (HAs). The successful development of these Nbs demonstrates the potential of molecular modeling as a low-cost and time-efficient method for engineering effective Nbs against SARS-CoV-2. The engineered Nbs have the potential to be employed in RBD-neutralizing assays, facilitating the identification of novel treatment, prevention, and diagnostic strategies against SARS-CoV-2.
COVID-19 大流行迫切需要有效的治疗和诊断策略来应对由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起的疾病。然而，众多令人关注的变异株（VOCs）的出现使得开发广泛特异性中和病毒的靶向治疗变得具有挑战性。在这项研究中，我们旨在使用计算技术开发能够有效中和 SARS-CoV-2 VOCs 受体结合域（RBD）的中和纳米体（Nbs）。我们评估了不同蛋白质-蛋白质对接程序的性能，并确定 HDOCK 是最适合 Nb/RBD 对接的程序，具有高精度。使用这种方法，我们设计了 14 种新型 Nbs，它们与 VOC RBDs 具有高结合亲和力。这些 Nbs 经过突变氨基酸修饰，与 RBDs 的关键氨基酸相互作用，导致结合亲和力高于人类血管紧张素转换酶 2（ACE2）和其他病毒 RBDs 或血凝素（HAs）。这些 Nbs 的成功开发证明了分子建模作为一种低成本、高效的工程有效 Nbs 来对抗 SARS-CoV-2 的方法具有潜力。这些工程 Nbs 有可能用于 RBD 中和测定，有助于鉴定针对 SARS-CoV-2 的新型治疗、预防和诊断策略。
