4.7 Article

Structure-Based Development of SARS-CoV-2 Spike Interactors

期刊

出版社

MDPI
DOI: 10.3390/ijms23105601

关键词

SARS-CoV-2; COVID-19; viral entry; spike protein; protein structure; infectious disease

资金

  1. project DELETE_COVID (DEveLopmEnT of a rapid biosEnsor against COVID19) [FISR2020IP_00014]
  2. RECOVER-COVID19 (RicErCa e sviluppO VERsus COVID19 in Campania), POR FESR CAMPANIA [1.3 -2020-2021]
  3. CINECA Supercomputing (framework ISCRA@CINECA-project) [HP10CSBSQC]

向作者/读者索取更多资源

The study engineered stable S-plug molecules through a computational approach to potentially inhibit viral entry by interfering with the interaction between SARS-CoV-2 spike protein and ACE2. These molecules have high stability and affinity to the spike protein, providing a solid foundation for the development of therapeutic and diagnostic tools against ACE2-accessing coronaviruses.
Coronaviruses, including SARS-CoV-2 (the etiological agent of the current COVID-19 pandemic), rely on the surface spike glycoprotein to access the host cells, mainly through the interaction of their receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2). Therefore, molecular entities able to interfere with the binding of the SARS-CoV-2 spike protein to ACE2 have great potential to inhibit viral entry. Starting from the available structural data on the interaction between SARS-CoV-2 spike protein and the host ACE2 receptor, we engineered a set of soluble and stable spike interactors, here denoted as S-plugs. Starting from the prototype S-plug, we adopted a computational approach by combining stability prediction, associated to single-point mutations, with molecular dynamics to enhance both S-plug thermostability and binding affinity to the spike protein. The best developed molecule, S-plug3, possesses a highly stable alpha-helical con-formation (with melting temperature Tm of 54 degrees C) and can interact with the spike RBD and S1 domains with similar low nanomolar affinities. Importantly, S-plug3 exposes the spike RBD to almost the same interface as the human ACE2 receptor, aimed at the recognition of all ACE2-accessing coronaviruses. Consistently, S-plug3 preserves a low nanomolar dissociation constant with the delta B.1.617.2 variant of SARS-CoV-2 spike protein (K-D = 29.2 +/- 0.6 nM). Taken together, we provide valid starting data for the development of therapeutical and diagnostic tools against coronaviruses accessing through ACE2.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据