More Like this

1. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

   https://doi.org/10.1073/pnas.2010146117  

   Damas, Joana ; Hughes, Graham M. ; Keough, Kathleen C. ; Painter, Corrie A. ; Persky, Nicole S. ; Corbo, Marco ; Hiller, Michael ; Koepfli, Klaus-Peter ; Pfenning, Andreas R. ; Zhao, Huabin ; et al ( September 2020 , Proceedings of the National Academy of Sciences)

   null (Ed.)

   The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care. 

   more » « less
2. De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain

   https://doi.org/10.1039/D3MD00222E  

   Thakkar, Ravindra ; Agarwal, Dilip K ; Ranaweera, Chathuranga B ; Ishiguro, Susumu ; Conda-Sheridan, Martin ; Gaudreault, Natasha N ; Richt, Juergen A ; Tamura, Masaaki ; Comer, Jeffrey ( September 2023 , RSC Medicinal Chemistry)

   Binding configuration of a de novo stapled peptide on SARS-CoV-2 spike protein, as predicted by molecular simulation. Stapled residues enhance peptide stability while interacting residues engage key amino acids on the protein receptor-binding domain. 

   more » « less
3. Extracellular Vimentin as a Target Against SARS‐CoV‐2 Host Cell Invasion

   https://doi.org/10.1002/smll.202105640  

   Suprewicz, Łukasz ; Swoger, Maxx ; Gupta, Sarthak ; Piktel, Ewelina ; Byfield, Fitzroy J. ; Iwamoto, Daniel V. ; Germann, Danielle ; Reszeć, Joanna ; Marcińczyk, Natalia ; Carroll, Robert J. ; et al ( December 2021 , Small)

   Infection of human cells by pathogens, including SARS‐CoV‐2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS‐CoV‐2 is the angiotensin‐converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co‐receptors that mediate binding and host cell invasion by SARS‐CoV‐2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS‐CoV‐2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS‐CoV‐2 spike protein, and antibodies against vimentin block in vitro SARS‐CoV‐2 pseudovirus infection of ACE2‐expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co‐receptor for SARS‐CoV‐2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS‐CoV‐2 spike protein‐ACE2 complex in mediating SARS‐CoV‐2 cell entry, and vimentin‐targeting agents may yield new therapeutic strategies for preventing and slowing SARS‐CoV‐2 infection.

    

   more » « less
4. Probing the mutational landscape of the SARS-CoV-2 spike protein via quantum mechanical modeling of crystallographic structures

   https://doi.org/10.1093/pnasnexus/pgac180  

   Zaccaria, Marco ; Genovese, Luigi ; Dawson, William ; Cristiglio, Viviana ; Nakajima, Takahito ; Johnson, Welkin ; Farzan, Michael ; Momeni, Babak ( November 2022 , PNAS Nexus)

   Nelson, Karen E (Ed.)

   Abstract We employ a recently developed complexity-reduction quantum mechanical (QM-CR) approach, based on complexity reduction of density functional theory calculations, to characterize the interactions of the SARS-CoV-2 spike receptor binding domain (RBD) with ACE2 host receptors and antibodies. QM-CR operates via ab initio identification of individual amino acid residue’s contributions to chemical binding and leads to the identification of the impact of point mutations. Here, we especially focus on the E484K mutation of the viral spike protein. We find that spike residue 484 hinders the spike's binding to the human ACE2 receptor (hACE2). In contrast, the same residue is beneficial in binding to the bat receptor Rhinolophus macrotis ACE2 (macACE2). In agreement with empirical evidence, QM-CR shows that the E484K mutation allows the spike to evade categories of neutralizing antibodies like C121 and C144. The simulation also shows how the Delta variant spike binds more strongly to hACE2 compared to the original Wuhan strain, and predicts that a E484K mutation can further improve its binding. Broad agreement between the QM-CR predictions and experimental evidence supports the notion that ab initio modeling has now reached the maturity required to handle large intermolecular interactions central to biological processes. 

   more » « less
5. Systemic effects of missense mutations on SARS-CoV-2 spike glycoprotein stability and receptor-binding affinity

   https://doi.org/10.1093/bib/bbaa233  

   Teng, Shaolei ; Sobitan, Adebiyi ; Rhoades, Raina ; Liu, Dongxiao ; Tang, Qiyi ( March 2021 , Briefings in Bioinformatics)

   null (Ed.)

   Abstract The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18 354 mutations in S protein were analyzed, and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3705 mutations in SARS-CoV-2 RBD and 11 324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD–ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19. 

   more » « less