United States Department of Agriculture, Agricultural Research Service, Southern Regional Research Center (USDA-ARS-SRRC), New Orleans, LA 70124, USA.
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA.
Molecules. 2022 Mar 23;27(7):2070. doi: 10.3390/molecules27072070.
The global burden of the SARS-CoV-2 pandemic is thought to result from a high viral transmission rate. Here, we consider mechanisms that influence host cell-virus binding between the SARS-CoV-2 spike glycoprotein (SPG) and the human angiotensin-converting enzyme 2 (ACE2) with a series of peptides designed to mimic key ACE2 hot spots through adopting a helical conformation analogous to the N-terminal α1 helix of ACE2, the region experimentally shown to bind to the SARS-CoV-2 receptor-binding domain (RBD). The approach examines putative structure/function relations by assessing SPG binding affinity with surface plasmon resonance (SPR). A cyclic peptide (c[KFNHEAEDLFEKLM]) was characterized in an α-helical conformation with micromolar affinity (KD = 500 µM) to the SPG. Thus, stabilizing the helical structure of the 14-mer through cyclization improves binding to SPG by an order of magnitude. In addition, end-group peptide analog modifications and residue substitutions mediate SPG binding, with net charge playing an apparent role. Therefore, we surveyed reported viral variants, and a correlation of increased positive charge with increased virulence lends support to the hypothesis that charge is relevant to enhanced viral fusion. Overall, the structure/function relationship informs the importance of conformation and charge for virus-binding analog design.
我们认为，SARS-CoV-2 大流行的全球负担是由高病毒传播率造成的。在这里，我们通过采用类似于 ACE2 N 端α1 螺旋的螺旋构象，设计了一系列模拟 ACE2 热点的肽，来研究影响 SARS-CoV-2 刺突糖蛋白（SPG）与人类血管紧张素转换酶 2（ACE2）之间宿主细胞-病毒结合的机制，该区域经实验证明与 SARS-CoV-2 受体结合域（RBD）结合。该方法通过表面等离子体共振（SPR）评估 SPG 结合亲和力来检查假定的结构/功能关系。一种环状肽（c[KFNHEAEDLFEKLM]）被表征为具有微摩尔亲和力（KD = 500 µM）的α-螺旋构象与 SPG 结合。因此，通过环化稳定 14 肽的螺旋结构可使结合 SPG 的能力提高一个数量级。此外，末端基团肽类似物修饰和残基取代介导 SPG 结合，净电荷显然起着作用。因此，我们研究了报道的病毒变体，阳性电荷增加与毒力增加之间的相关性支持了这样一种假设，即电荷与增强的病毒融合有关。总的来说，结构/功能关系表明构象和电荷对于病毒结合模拟设计的重要性。
