Structure-Based Development of SARS-CoV-2 Spike Interactors
| Autor: | Flavia Squeglia, Maria Romano, Luciana Esposito, Giovanni Barra, Pietro Campiglia, Marina Sala, Maria Carmina Scala, Alessia Ruggiero, Rita Berisio |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Membrane Glycoproteins
SARS-CoV-2 Organic Chemistry COVID-19 General Medicine Peptidyl-Dipeptidase A Catalysis Computer Science Applications Inorganic Chemistry Viral Envelope Proteins Spike Glycoprotein Coronavirus Humans viral entry spike protein protein structure infectious disease Angiotensin-Converting Enzyme 2 Physical and Theoretical Chemistry Molecular Biology Pandemics Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 10; Pages: 5601 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23105601 |
| Popis: | 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 α-helical con-formation (with melting temperature Tm of 54 °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 (KD = 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. |
| Databáze: | OpenAIRE |
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