Structure/Function Analysis of Truncated Amino-Terminal ACE2 Peptide Analogs That Bind to SARS-CoV-2 Spike Glycoprotein

Molecules

E. Berk Atuk¹  Janarthanan Jayawickramarajah¹  Noah Beltrami¹  Robert T. Mackin²  J. Vincent Edwards²  Brian D. Condon²  Alfred D. French² 

[1] Department of Chemistry, Tulane University, New Orleans, LA 70118, USA;United States Department of Agriculture, Agricultural Research Service, Southern Regional Research Center (USDA-ARS-SRRC), New Orleans, LA 70124, USA;

关键词: SARS-CoV-2;    COVID-19;    cyclic peptide;    helical peptide;    surface plasmon resonance;   

DOI  :  10.3390/molecules27072070

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown