Biophysical principles predict fitness of SARS-CoV-2 variants DOI Creative Commons
D. I. C. Wang, Marian Huot, Vaibhav Mohanty

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 24, 2023

Abstract SARS-CoV-2 employs its spike protein’s receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected immune responses, while requiring efficient cell receptors for successful infection. However, our understanding of how RBD’s biophysical properties contribute SARS-CoV-2’s epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis variants and the discovery function based on thermodynamics, we unravel relationship between their contribution viral fitness. We developed model that uses statistical mechanics map molecular phenotype space, characterized by constants ACE2, LY-CoV016, LY-CoV555, REGN10987, S309, onto epistatic landscape. validate findings through experimentally measured machine learning (ML) estimated affinities, coupled with infectivity data derived from population-level sequencing. Our reveals this effectively predicts novel can account interactions among mutations, including explaining later reversal Q493R. study sheds light impact specific mutations delivers tool predicting future trajectory previously unseen or emerging low frequency variants. These insights offer not only greater evolution but also potentially aid in guiding public health decisions battle against COVID-19 pandemics. Significance Statement This research presents maps into an By linking affinities virus epidemic fitness, powerful emergence success new model, validated real-world informed theoretical insights, provides foundation interpreting evolutionary past pandemics those future. adaptability extends key proteins other viruses as well, signifying potential interventions, advancing evolution.

Language: Английский

Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme DOI Creative Commons

Ann Varghese,

Jie Liu,

Bailang Liu

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(3), P. 491 - 491

Published: Jan. 23, 2025

The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage immune evasion, making it prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures PLpro complexed ligands deposited Protein Data Bank, offering valuable insight into ligand-binding features that could aid discovery development effective treatments targeting PLpro. In this study, we reviewed analyzed these 3D structures, focusing on key residues involved ligand interactions. Our analysis revealed most bind to PLpro’s substrate recognition sites S3/S4 SUb2. While are highly attractive extensively explored, other potential binding regions, such SUb1 Zn(II) domain, less explored may hold untapped future drug development. structural provides insights molecular accelerate therapeutics essential enzyme.

Language: Английский

Citations

0
Replication Features of SARS-CoV-2 and Advantages of Targeting S Protein with Aptamers to Block Viral Entry DOI Creative Commons
Jun Zheng,

Qiuxia Pang,

Zhaoying Fu

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus of the coronaviridae family. The enters cell through binding to corresponding receptor angiotensin-converting enzyme (ACE2) on host membrane with spike protein (S protein) its envelope; thus, we can design inhibitors that bind S block entry into cells. Aptamers are single stranded DNA or RNA molecules form specific three-dimensional structures and their target high affinity specificity thus promising candidates for inhibitors. This paper reviews replication cycle mechanisms SARS-CoV-2 as well preparation principle characteristics aptamers, features discussion advantages using aptamers prevent from infecting cells, finally summarizes research progress in protein-blocking aptamers.

Language: Английский

Citations

0
Epitopes of an antibody that neutralizes a wide range of SARS-CoV-2 variants in a conserved subdomain 1 of the spike protein DOI Creative Commons
Hanako Ishimaru, Mitsuhiro Nishimura, Hideki Shigematsu

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(5)

Published: April 16, 2024

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued, enabling the virus to escape from host immunity by changing its spike antigen, while biased toward receptor-binding domain and N-terminal domain. Here, we isolated a novel pan-SARS-CoV-2 neutralizing antibody (which named MO11) for even recent dominators XBB.1.16 EG.5.1, convalescent patient who had received three doses an original mRNA COVID-19 vaccination. A cryo-electron microscopy analysis spike-MO11 complex at 2.3 Å atomic resolution revealed that it recognizes conserved epitope hidden behind glycan shield N331 on subdomain 1 (SD1), holding both N- C-terminal segments comprising SD1. Our identification MO11 unveiled functional importance SD1 spike's function, discuss potential availability common among SARS-CoV-2 variants.IMPORTANCENovel variants with immune evasion ability are still repeatedly emerging, nonetheless, part developed in responding antigen earlier retains efficacy against irrespective numerous mutations. In exploration broadly effective antibodies, identified cross-neutralizing antibody, MO11, B cells patient. targets (SD1) was all emerging including EG.5.1. activity covering D614G EG.5.1 explained conservation epitope, regulating function viral infection. Demonstrated implies basal contribution such group antibodies prophylaxis COVID-19.

Language: Английский

Citations

3
Structural review of SARS-CoV-2 antiviral targets DOI Creative Commons
Wen Cui, Yinkai Duan, Gao Yan

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(9), P. 1301 - 1321

Published: Sept. 1, 2024

Language: Английский

Citations

3
Developing a SARS-CoV-2 main protease binding prediction random forest model for drug repurposing for COVID-19 treatment DOI Open Access
Jie Liu, Liang Xu, Wenjing Guo

et al.

Experimental Biology and Medicine, Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 24, 2023

The coronavirus disease 2019 (COVID-19) global pandemic resulted in millions of people becoming infected with the severe acute respiratory syndrome 2 (SARS-CoV-2) virus and close to seven million deaths worldwide. It is essential further explore design effective COVID-19 treatment drugs that target main protease SARS-CoV-2, a major for drugs. In this study, machine learning was applied predicting SARS-CoV-2 binding Food Drug Administration (FDA)-approved assist identification potential repurposing candidates treatment. Ligands bound Protein Data Bank compounds experimentally tested assays literature were curated. These chemicals divided into training (516 chemicals) testing (360 data sets. To identify binders as treat COVID-19, 1188 FDA-approved from Liver Toxicity Knowledge Base obtained. A random forest algorithm used constructing predictive models based on molecular descriptors calculated using Mold2 software. Model performance evaluated 100 iterations fivefold cross-validations which 78.8% balanced accuracy. model constructed whole dataset predict set applicability domain prediction confidence predicted discovered 10 COVID-19. Our results demonstrate an efficient method drug and, thus, may accelerate development targeting SARS-CoV-2.

Language: Английский

Citations

7
Fangchinoline inhibits SARS-CoV-2 and MERS-CoV entry DOI

Srikanth Sadhu,

Jyotsna Dandotiya,

Rajdeep Dalal

et al.

Antiviral Research, Journal Year: 2023, Volume and Issue: 220, P. 105743 - 105743

Published: Nov. 8, 2023

Language: Английский

Citations

6
Weak Value Amplification Based Optical Sensor for High Throughput Real-Time Immunoassay of SARS-CoV-2 Spike Protein DOI Creative Commons
Xiaonan Zhang, Lizhong Zhang,

Han Li

et al.

Biosensors, Journal Year: 2024, Volume and Issue: 14(7), P. 332 - 332

Published: July 8, 2024

The demand for accurate and efficient immunoassays calls the development of precise, high-throughput analysis methods. This paper introduces a novel approach utilizing weak measurement interface sensor immunoassays, offering solution high throughput analysis. Weak is precise quantum method that amplifies value system in interaction through appropriate pre- post-selection states. To facilitate simultaneous multiple samples, we have developed chip with six flow channels capable conducting concurrently. We can perform real-time immunoassay to determine binding characteristics spike protein antibody channel images calculating relative intensity. proposed boasts simple structure, eliminating need intricate nano processes. concentration intensity curve were fitted using Log-Log fitting regression equation, R2 was 0.91. Utilizing pre-transformation account slight variations detection sensitivity across different channels, present achieves an impressive limit detection(LOD) 0.85 ng/mL SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein, standard deviation 5.61. Furthermore, this has been successfully verified monitoring molecular-specific processes differentiating capacities.

Language: Английский

Citations

1
Comparative Computational Analysis of Spike Protein Structural Stability in SARS-CoV-2 Omicron Subvariants DOI Open Access
Anand Balupuri, Jeong‐Min Kim,

Kwang-Eun Choi

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(22), P. 16069 - 16069

Published: Nov. 8, 2023

The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike (S) protein mutations pose serious threats to current disease 2019 (COVID-19) therapies. A comprehensive understanding the structural stability SARS-CoV-2 is vital for development effective therapeutic strategies as it can offer valuable insights into their potential impact on viral infectivity. S mediates a virus' attachment host cells by binding angiotensin-converting enzyme (ACE2) through its receptor-binding domain (RBD), and in this affect affinity. We analyzed various Omicron subvariants computationally. Notably, sequences work were obtained directly from our own sample collection. evaluated free energy between ACE2 several complex forms. Additionally, we measured distances RBD each chain analyze conformational changes. Unlike most prior studies, full-length protein-ACE2 complexes instead only RBD-ACE2 complexes. including BA.1, BA.2, BA.2.12.1, BA.4/BA.5, BA.2.75, BA.2.75_K147E, BA.4.6 BA.4.6_N658S showed enhanced compared wild type, potentially due distinct mutations. Among them, BA.2.75 exhibited highest lowest level stability, respectively.

Language: Английский

Citations

2
Phase Separation-based Antiviral Decoy Particles as Basis for Programmable Broad-spectrum Therapeutics DOI Open Access
Or Willinger, Naor Granik, Sarah Goldberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 28, 2024

Abstract To gain access to cells, viruses employ host proteins as receptors. In soluble form, these receptors are used decoys inhibit infection. We fused candidate an RNA-binding protein, and using synthetic long non-coding RNA (slncRNA) cassettes that can undergo phase-separation we scaffolded the receptor fusions generate antiviral decoy particles. Using confocal microscopy, screened protein candidates by observing changes in morphology when incubated with viral-mimicking components. demonstrated ACE2 particles bind strongly coronavirus RBD, facilitating FRET, while sufficiently sialylated form agglutinated structures peripheries presence of a sialolectin. Infection assays show fully Delta Omicron BA.1 variants, LAMP1 GYPA significantly reduce influenza infection in-cellulo . This work establishes foundation for broad-spectrum particles, composed multiple targeting various viruses.

Language: Английский

Citations

0
Biophysical principles predict fitness of SARS-CoV-2 variants DOI Creative Commons
D. I. C. Wang, Marian Huot, Vaibhav Mohanty

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 24, 2023

Abstract SARS-CoV-2 employs its spike protein’s receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected immune responses, while requiring efficient cell receptors for successful infection. However, our understanding of how RBD’s biophysical properties contribute SARS-CoV-2’s epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis variants and the discovery function based on thermodynamics, we unravel relationship between their contribution viral fitness. We developed model that uses statistical mechanics map molecular phenotype space, characterized by constants ACE2, LY-CoV016, LY-CoV555, REGN10987, S309, onto epistatic landscape. validate findings through experimentally measured machine learning (ML) estimated affinities, coupled with infectivity data derived from population-level sequencing. Our reveals this effectively predicts novel can account interactions among mutations, including explaining later reversal Q493R. study sheds light impact specific mutations delivers tool predicting future trajectory previously unseen or emerging low frequency variants. These insights offer not only greater evolution but also potentially aid in guiding public health decisions battle against COVID-19 pandemics. Significance Statement This research presents maps into an By linking affinities virus epidemic fitness, powerful emergence success new model, validated real-world informed theoretical insights, provides foundation interpreting evolutionary past pandemics those future. adaptability extends key proteins other viruses as well, signifying potential interventions, advancing evolution.

Language: Английский

Citations

0