Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Shah, Masaud; Ahmad, Bilal; Choi, Sangdun; Woo, Hyun Goo

doi:10.21203/rs.3.rs-16932/v1

Cited by 12 publications

(14 citation statements)

References 30 publications

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“…Two amino acid stretches of 445-456 and 488-501 which participate in ACE2 binding, were truncated from the RBD and joined through flexible linker, LIGRGP, to optimally orient the joining peptides and retain its target-binding ability. In its resting (RBD down ) position, the same sheet-loop-sheet motif lays between the NTD and the RBD domains of the adjustment S protomer, as we have shown previously (30). Thus, in addition to ACE2-RBD hindrance, we suggest that CSNP4 can present RBD for the immune surveillance by limiting its spontaneous position switching.…”

Section: Design Of the Candidate Csnpssupporting

confidence: 75%

“…In the current study, we attempted similar approaches to design structurally constrained peptides, which could address the above-mentioned paradoxes of the spontaneous RBD-conformation switching and the interaction of S1 with soluble and membrane bound ACE2. We and others have delineated the ACE2-RBD interface and identified key residues that contribute to the binding strength of ACE2-RBD (15,17,18,30). Point mutation analyses could confirm that some of these residues are vital to the ACE2-RBD interface (31).…”

Section: Introductionmentioning

confidence: 88%

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Pharmacophore-based peptide biologics neutralize SARS-CoV-2 S1 and deter S1-ACE2 interactionin vitro

Woo

Shah

Moon

2020

Preprint

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Effective therapeutics and stable vaccine are the urgent need of the day to combat COVID-19 pandemic. SARS-CoV-2 spike protein has a pivotal role in cell-entry and host immune response, thus regarded as potential drug- and vaccine-target. As the virus utilizes the S1 domain of spike to initiate cell-attachment and S2 domain for membrane fusion, several attempts have been made to design viral-receptor and viral-fusion blockers. Here, by deploying interactive structure-based design and pharmacophore-based approaches, we designed short and stable peptide-biologics i.e. CoV-spike-neutralizing peptides (CSNPs) including CSNP1, CSNP2, CSNP3, CSNP4. We could demonstrate in cell culture experiments that CSNP2 binds to S1 at submicromolar concentration and abrogates the S1-hACE2 interaction. CSNP3, a modified and downsized form of CSNP2, could neither interfere with the S1-hACE2 interaction nor bind to S1. CSNP4 exhibited dose-dependent binding to both S1 and hACE2 and abolished the S1-hACE2 interaction in vitro. CSNP4 possibly enhance the mAb-based S1 neutralization by limiting the spontaneous movement of spike receptor-binding domain (RBD), whereas CSNP2 allowed RBD-mAb binding without any steric hindrance. Taken together, we suggest that CSNP2 and CSNP4 are potent and stable candidate peptides that can neutralize the SARS-CoV-2 spike and possibly pose the virus to host immune surveillance.

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Section: Design Of the Candidate Csnpssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 88%

Pharmacophore-based peptide biologics neutralize SARS-CoV-2 S1 and deter S1-ACE2 interactionin vitro

Woo

Shah

Moon

2020

Preprint

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“…The sequence conservation of S1 RBD yielded ≈73% identity, while the RBM region involved in direct interactions with the ACE2 receptor displayed a more significant variability as similarity between SARS-CoV and SARS-CoV-2 sequences dropped to ≈50% ( Figure 2 ). This analysis is fully consistent with previous studies [ 40 , 41 , 42 ] suggesting that a significant sequence variability of the SARS-CoV interacting residues from RBM motif may be accompanied by the corresponding local conformational changes. Structural studies confirmed these assertions revealing small but important changes in the RBM residues of SARS-CoV-RBD and SARS-CoV-2-RBD proteins [ 21 , 22 , 23 , 24 , 25 , 26 ].…”

Section: Resultssupporting

confidence: 92%

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Verkhivker

2020

IJMS

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Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus–host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein–protein interfaces responsible for virus entry and infection transmission.

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“…It is suggested that this situation may be effective in the higher transmission rate of SARS-CoV-2 than SARS-CoV. In addition, the transformation of Pro-Ala475 and insertion of Gly482 into the AGSTPCNGV ring of RBD has prevented the neutralization of SARS-CoV-2 by anti-SARS-CoV mAbs 31 .…”

Section: Sars-cov-2 Mutationsmentioning

confidence: 99%

Mutations Observed in the SARS-CoV-2 Spike Glycoprotein and Their Effects in the Interaction of Virus with ACE-2 Receptor

Durmaz¹,

Abdulmajed²,

Durmaz³

2020

MMJ

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Coronaviruses (CoVs) classified in the Coronaviridae family infect a very large spectrum of vertebrate group. Seven CoVs that cause human disease consist of Alpha-CoVs, which are HCoV-229E, and NL63 and beta-CoVs, which are MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-HKU1, and SARS-CoV-2. SARS-CoV-2 is an enveloped, positive-polarity, single-stranded RNA virus responsible for a new Coronavirus disease 2019 (COVID-19). The mutagenic ability of the SARS-CoV-2 directs its evolution and genome variability, thus allowing viruses to escape from host immunity and develop drug resistance. Tracing viral mutations is also important for the development of new vaccines, antiviral drugs, and diagnostic systems. During replication in the host cell, genomic mutations occur in the virus and these mutations are transferred to new generations. For this reason, systematic monitoring of mutations in the SARS-CoV-2 genome allows observation of the national and international molecular epidemiology of the virus. SARS-CoV-2 spike (S) glycoprotein is vital in the binding of the virus to the host cell receptor that is angiotensin converting-enzyme 2 (ACE2), membrane fusion, vaccine studies and immune response to the virus. Therefore, mutations in the gene encoding the S glycoprotein and especially the possible variations in the receptor binding domain (RBD) in S gene are important issues to be emphasized. In this article, information about the mutations observed in the SARS-CoV-2 S glycoprotein and their possible effects are presented.

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Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Cited by 12 publications

References 30 publications

Pharmacophore-based peptide biologics neutralize SARS-CoV-2 S1 and deter S1-ACE2 interactionin vitro

Pharmacophore-based peptide biologics neutralize SARS-CoV-2 S1 and deter S1-ACE2 interactionin vitro

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Mutations Observed in the SARS-CoV-2 Spike Glycoprotein and Their Effects in the Interaction of Virus with ACE-2 Receptor

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