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

Abstract

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.

A computational approach to rapidly design peptides that detect SARS-CoV-2 surface protein S

“…Recently, Squeglia et al. ( 37 ) combined molecular docking with single point mutations and molecular dynamics to design high affinity S protein binder, where a series of peptides against the S protein had a binding affinity in the range of 29–200 nM.…”

Evaluation of SARS-CoV-2 ORF7a Deletions from COVID-19-Positive Individuals and Its Impact on Virus Spread in Cell Culture

“…The most common changes in SARS-CoV-2 are single nucleotide substitutions (SNSs), although insertions and deletions have also been reported [ 13 , 14 ]. Single nucleotide variants (SNVs) are found in various sites on non-structural genes that code for 16 nsp on the first 2/3 of the SARS genome as well on structural proteins as S, which is responsible for recognition of the host receptor protein [ 15 , 16 ]. Most of these single nucleotide variants cause synonymous mutation [ 17 ], which may be selected due to a better fit or increasing pathogenicity.…”

Understanding Molecular Actors of SARS-CoV-2 Virulence to Tackle COVID-19 Outbreak

“…Another factor that is mandatory for SARS-CoV-2 infection is the viral access to the host cells through the Spike protein. As it is essential for infection, the spike protein has been exploited as a target for vaccine development [ 2 ], functioning as a target of the neutralizing antibodies and interactors [ 3 , 4 , 5 ]. Hatmal et al performed an in-depth review of the literature, covering the structural and mutational aspects of the spike protein in the context of SARS-CoV-2 and compared these with those of SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) [ 6 ].…”